Human genome, chromosomes

Human genome, chromosomes

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I have a very basic question, but it seems the hardest to me. So we have 46 chromosomes (23, 2 copies of each). Do all chromosomes have the same DNA? If so, does it mean that in different cells with different functions some genes are expressed and some aren't? Also, if each chromosome has different lets say "fragment" of the genome, how is the genome interconnected?

Do all chromosomes have the same DNA?

No. Not any more than each chapter of a book has the same words in the same order.

If so, does it mean that in different cells with different functions some genes are expressed and some aren't?

Yes. In general, all cells in your body have all the same DNA; what makes your retina cells function differently from your pancreatic beta cells is which genes they express. Like if every chef in a restaurant had the same recipe book which had every recipe the restaurant can make, but the pastry chef only makes pastries.

Also, if each chromosome has different lets say "fragment" of the genome, how is the genome interconnected?

The genome is not physically connected except for all the genes on a chromosome being physically connected. But a gene product from one chromosome might control expression of another gene by physically binding to the DNA close to it, which can affect its expression. But most gene-gene interactions are really protein-protein interactions. (Or in some cases, RNA interacting with RNA)

Human Genome Project

The original impetus for the HGP came from the U.S. Department of Energy (DOE) shortly after World War II. In 1945 there were many survivors of the atomic bombs dropped on Hiroshima and Nagasaki who had been exposed to high levels of radiation. In 1946 geneticist and Nobel Prize winner H.J. Müller opined in the New York Times that "if they could foresee the results [mutations among their descendants] 1,000 years from now . . . they might consider themselves more fortunate if the bomb had killed them." Müller, who had studied the biological effects of radiation on the fruit fly Drosophila melanogaster, had firsthand experience with the devastating effects of radiation. The survivors of the bomb were considered poor marriage prospects, because of the potential of carrying mutations and were often ostracized by Japanese society. Thus the Atomic Energy Commission (AEC) of the DOE set up an Atomic Bomb Casualty Commission in 1947 to address the issue of potential mutations among the survivors. The problem they faced, though, was how to experimentally determine such mutations. It would be many years before the technology was developed to do so.

During the mid-1970s, molecular biologists developed techniques for the isolation and cloning of individual genes. In 1977 Walter Gilbert and Fred Sanger independently developed methods for the sequencing of DNA, for which they received the Nobel Prize. In 1980, the polymerase chain reaction (PCR) was invented by a scientist at Cetus Corporation. This technique allowed one to take minute samples of DNA and amplify them a billionfold for analysis. In 1986, an automated DNA sequencer was developed, increasing the number of bases sequenced per day. Thus, by the mid-1980s, there was a feeling among molecular biologists that it might now be feasible to sequence the entire human genome. The first major impetus came in June 1985 when Robert Sinsheimer, chancellor of the University of California at Santa Cruz, called a meeting among leading scientists to discuss the possibility of sequencing the human genome. Meanwhile, the DOE, led by Charles Delisi, was a strong supporter of the initiative, for the DOE had a continuing interest in identifying radiation-caused mutations. Sequencing the entire genome would clearly provide the best way to analyze such mutations.

Many biologists were interested in this "Holy Grail of Molecular Biology." Most notably was Walter Gilbert who, through his interest, personality, and academic ties, developed enormous enthusiasm for the project. The initial goals were to develop:

  • • genetic linkage maps
  • • a physical map of ordered clones of DNA sequences
  • • the capacity for large-scale sequencing, as faster and cheaper machines and great leaps in technology would be necessary.

By 1990 the Human Genome Project had received the endorsement of the National Academy of Sciences, the National Research Council, the DOE, the National Institutes of Health (NIH), the National Science Foundation, the U.S. Department of Agriculture, and the Howard Hughes Medical Institute. Sequencing of the human genome was now officially begun. Nobel Prize winner James Watson agreed to head the project at the NIH. It was estimated to cost $3 billion and be completed by September 30, 2005. However, Watson resigned as the director of the HGP over the issue of patenting the genome. Francis Collins succeeded him as director. Just as important was the establishment of projects seeking to sequence several model organisms, that is, those organisms of genetic, biochemical, or medical importance.


The first human genome sequences were published in nearly complete draft form in February 2001 by the Human Genome Project [15] and Celera Corporation. [16] Completion of the Human Genome Project's sequencing effort was announced in 2004 with the publication of a draft genome sequence, leaving just 341 gaps in the sequence, representing highly-repetitive and other DNA that could not be sequenced with the technology available at the time. [8] The human genome was the first of all vertebrates to be sequenced to such near-completion, and as of 2018, the diploid genomes of over a million individual humans had been determined using next-generation sequencing. [17] In 2021 it was reported that the T2T consortium had filled in all of the gaps. Thus there came into existence a complete human genome with no gaps. [18]

These data are used worldwide in biomedical science, anthropology, forensics and other branches of science. Such genomic studies have led to advances in the diagnosis and treatment of diseases, and to new insights in many fields of biology, including human evolution.

In June 2016, scientists formally announced HGP-Write, a plan to synthesize the human genome. [19] [20]

Although the 'completion' of the human genome project was announced in 2001, [14] there remained hundreds of gaps, with about 5–10% of the total sequence remaining undetermined. The missing genetic information was mostly in repetitive heterochromatic regions and near the centromeres and telomeres, but also some gene-encoding euchromatic regions. [21] There remained 160 euchromatic gaps in 2015 when the sequences spanning another 50 formerly-unsequenced regions were determined. [22] Only in 2020 was the first truly complete telomere-to-telomere sequence of a human chromosome determined, namely of the X chromosome. [23]

The total length of the human reference genome, that does not represent the sequence of any specific individual, is over 3 billion base pairs. The genome is organized into 22 paired chromosomes, termed autosomes, plus the 23rd pair of sex chromosomes (XX) in the female, and (XY) in the male. These are all large linear DNA molecules contained within the cell nucleus. The genome also includes the mitochondrial DNA, a comparatively small circular molecule present in multiple copies in each the mitochondrion.

Human reference genome data, by chromosome [24]
Chromosome Length
Variations Protein-
miRNA rRNA snRNA snoRNA Misc
Links Centromere
1 85 248,956,422 12,151,146 2058 1220 1200 496 134 66 221 145 192 EBI 125 7.9
2 83 242,193,529 12,945,965 1309 1023 1037 375 115 40 161 117 176 EBI 93.3 16.2
3 67 198,295,559 10,638,715 1078 763 711 298 99 29 138 87 134 EBI 91 23
4 65 190,214,555 10,165,685 752 727 657 228 92 24 120 56 104 EBI 50.4 29.6
5 62 181,538,259 9,519,995 876 721 844 235 83 25 106 61 119 EBI 48.4 35.8
6 58 170,805,979 9,130,476 1048 801 639 234 81 26 111 73 105 EBI 61 41.6
7 54 159,345,973 8,613,298 989 885 605 208 90 24 90 76 143 EBI 59.9 47.1
8 50 145,138,636 8,221,520 677 613 735 214 80 28 86 52 82 EBI 45.6 52
9 48 138,394,717 6,590,811 786 661 491 190 69 19 66 51 96 EBI 49 56.3
10 46 133,797,422 7,223,944 733 568 579 204 64 32 87 56 89 EBI 40.2 60.9
11 46 135,086,622 7,535,370 1298 821 710 233 63 24 74 76 97 EBI 53.7 65.4
12 45 133,275,309 7,228,129 1034 617 848 227 72 27 106 62 115 EBI 35.8 70
13 39 114,364,328 5,082,574 327 372 397 104 42 16 45 34 75 EBI 17.9 73.4
14 36 107,043,718 4,865,950 830 523 533 239 92 10 65 97 79 EBI 17.6 76.4
15 35 101,991,189 4,515,076 613 510 639 250 78 13 63 136 93 EBI 19 79.3
16 31 90,338,345 5,101,702 873 465 799 187 52 32 53 58 51 EBI 36.6 82
17 28 83,257,441 4,614,972 1197 531 834 235 61 15 80 71 99 EBI 24 84.8
18 27 80,373,285 4,035,966 270 247 453 109 32 13 51 36 41 EBI 17.2 87.4
19 20 58,617,616 3,858,269 1472 512 628 179 110 13 29 31 61 EBI 26.5 89.3
20 21 64,444,167 3,439,621 544 249 384 131 57 15 46 37 68 EBI 27.5 91.4
21 16 46,709,983 2,049,697 234 185 305 71 16 5 21 19 24 EBI 13.2 92.6
22 17 50,818,468 2,135,311 488 324 357 78 31 5 23 23 62 EBI 14.7 93.8
X 53 156,040,895 5,753,881 842 874 271 258 128 22 85 64 100 EBI 60.6 99.1
Y 20 57,227,415 211,643 71 388 71 30 15 7 17 3 8 EBI 10.4 100
mtDNA 0.0054 16,569 929 13 0 0 24 0 2 0 0 0 EBI N/A 100
total 3,088,286,401 155,630,645 20412 14600 14727 5037 1756 532 1944 1521 2213

Original analysis published in the Ensembl database at the European Bioinformatics Institute (EBI) and Wellcome Trust Sanger Institute. Chromosome lengths estimated by multiplying the number of base pairs by 0.34 nanometers (distance between base pairs in the most common structure of the DNA double helix a recent estimate of human chromosome lengths based on updated data reports 205.00 cm for the diploid male genome and 208.23 cm for female, corresponding to weights of 6.41 and 6.51 picograms (pg), respectively [25] ). Number of proteins is based on the number of initial precursor mRNA transcripts, and does not include products of alternative pre-mRNA splicing, or modifications to protein structure that occur after translation.

Variations are unique DNA sequence differences that have been identified in the individual human genome sequences analyzed by Ensembl as of December 2016. The number of identified variations is expected to increase as further personal genomes are sequenced and analyzed. In addition to the gene content shown in this table, a large number of non-expressed functional sequences have been identified throughout the human genome (see below). Links open windows to the reference chromosome sequences in the EBI genome browser.

Small non-coding RNAs are RNAs of as many as 200 bases that do not have protein-coding potential. These include: microRNAs, or miRNAs (post-transcriptional regulators of gene expression), small nuclear RNAs, or snRNAs (the RNA components of spliceosomes), and small nucleolar RNAs, or snoRNA (involved in guiding chemical modifications to other RNA molecules). Long non-coding RNAs are RNA molecules longer than 200 bases that do not have protein-coding potential. These include: ribosomal RNAs, or rRNAs (the RNA components of ribosomes), and a variety of other long RNAs that are involved in regulation of gene expression, epigenetic modifications of DNA nucleotides and histone proteins, and regulation of the activity of protein-coding genes. Small discrepancies between total-small-ncRNA numbers and the numbers of specific types of small ncNRAs result from the former values being sourced from Ensembl release 87 and the latter from Ensembl release 68.

The number of genes in the human genome is not entirely clear because the function of numerous transcripts remains unclear. This is especially true for non-coding RNA. The number of protein-coding genes is better known but there are still on the order of 1,400 questionable genes which may or may not encode functional proteins, usually encoded by short open reading frames.

Discrepancies in human gene number estimates among different databases, as of July 2018 [26]
Gencode [27] Ensembl [28] Refseq [29] CHESS [30]
protein-coding genes 19,901 20,376 20,345 21,306
lncRNA genes 15,779 14,720 17,712 18,484
antisense RNA 5501 28 2694
miscellaneous RNA 2213 2222 13,899 4347
Pseudogenes 14,723 1740 15,952
total transcripts 203,835 203,903 154,484 328,827

Information content Edit

The haploid human genome (23 chromosomes) is about 3 billion base pairs long and contains around 30,000 genes. [31] Since every base pair can be coded by 2 bits, this is about 750 megabytes of data. An individual somatic (diploid) cell contains twice this amount, that is, about 6 billion base pairs. Men have fewer than women because the Y chromosome is about 57 million base pairs whereas the X is about 156 million. Since individual genomes vary in sequence by less than 1% from each other, the variations of a given human's genome from a common reference can be losslessly compressed to roughly 4 megabytes. [32]

The entropy rate of the genome differs significantly between coding and non-coding sequences. It is close to the maximum of 2 bits per base pair for the coding sequences (about 45 million base pairs), but less for the non-coding parts. It ranges between 1.5 and 1.9 bits per base pair for the individual chromosome, except for the Y-chromosome, which has an entropy rate below 0.9 bits per base pair. [33]

The content of the human genome is commonly divided into coding and noncoding DNA sequences. Coding DNA is defined as those sequences that can be transcribed into mRNA and translated into proteins during the human life cycle these sequences occupy only a small fraction of the genome (<2%). Noncoding DNA is made up of all of those sequences (ca. 98% of the genome) that are not used to encode proteins.

Some noncoding DNA contains genes for RNA molecules with important biological functions (noncoding RNA, for example ribosomal RNA and transfer RNA). The exploration of the function and evolutionary origin of noncoding DNA is an important goal of contemporary genome research, including the ENCODE (Encyclopedia of DNA Elements) project, which aims to survey the entire human genome, using a variety of experimental tools whose results are indicative of molecular activity.

Because non-coding DNA greatly outnumbers coding DNA, the concept of the sequenced genome has become a more focused analytical concept than the classical concept of the DNA-coding gene. [34] [35]

Protein-coding sequences represent the most widely studied and best understood component of the human genome. These sequences ultimately lead to the production of all human proteins, although several biological processes (e.g. DNA rearrangements and alternative pre-mRNA splicing) can lead to the production of many more unique proteins than the number of protein-coding genes. The complete modular protein-coding capacity of the genome is contained within the exome, and consists of DNA sequences encoded by exons that can be translated into proteins. Because of its biological importance, and the fact that it constitutes less than 2% of the genome, sequencing of the exome was the first major milepost of the Human Genome Project.

Number of protein-coding genes. About 20,000 human proteins have been annotated in databases such as Uniprot. [37] Historically, estimates for the number of protein genes have varied widely, ranging up to 2,000,000 in the late 1960s, [38] but several researchers pointed out in the early 1970s that the estimated mutational load from deleterious mutations placed an upper limit of approximately 40,000 for the total number of functional loci (this includes protein-coding and functional non-coding genes). [39] The number of human protein-coding genes is not significantly larger than that of many less complex organisms, such as the roundworm and the fruit fly. This difference may result from the extensive use of alternative pre-mRNA splicing in humans, which provides the ability to build a very large number of modular proteins through the selective incorporation of exons.

Protein-coding capacity per chromosome. Protein-coding genes are distributed unevenly across the chromosomes, ranging from a few dozen to more than 2000, with an especially high gene density within chromosomes 1, 11, and 19. Each chromosome contains various gene-rich and gene-poor regions, which may be correlated with chromosome bands and GC-content. [40] The significance of these nonrandom patterns of gene density is not well understood. [41]

Size of protein-coding genes. The size of protein-coding genes within the human genome shows enormous variability. For example, the gene for histone H1a (HIST1HIA) is relatively small and simple, lacking introns and encoding an 781 nucleotide-long mRNA that produces a 215 amino acid protein from its 648 nucleotide open reading frame. Dystrophin (DMD) was the largest protein-coding gene in the 2001 human reference genome, spanning a total of 2.2 million nucleotides, [42] while more recent systematic meta-analysis of updated human genome data identified an even larger protein-coding gene, RBFOX1 (RNA binding protein, fox-1 homolog 1), spanning a total of 2.47 million nucleotides. [43] Titin (TTN) has the longest coding sequence (114,414 nucleotides), the largest number of exons (363), [42] and the longest single exon (17,106 nucleotides). As estimated based on a curated set of protein-coding genes over the whole genome, the median size is 26,288 nucleotides (mean = 66,577), the median exon size, 133 nucleotides (mean = 309), the median number of exons, 8 (mean = 11), and the median encoded protein is 425 amino acids (mean = 553) in length. [43]

Examples of human protein-coding genes [44]
Protein Chrom Gene Length Exons Exon length Intron length Alt splicing
Breast cancer type 2 susceptibility protein 13 BRCA2 83,736 27 11,386 72,350 yes
Cystic fibrosis transmembrane conductance regulator 7 CFTR 202,881 27 4,440 198,441 yes
Cytochrome b MT MTCYB 1,140 1 1,140 0 no
Dystrophin X DMD 2,220,381 79 10,500 2,209,881 yes
Glyceraldehyde-3-phosphate dehydrogenase 12 GAPDH 4,444 9 1,425 3,019 yes
Hemoglobin beta subunit 11 HBB 1,605 3 626 979 no
Histone H1A 6 HIST1H1A 781 1 781 0 no
Titin 2 TTN 281,434 364 104,301 177,133 yes

Noncoding DNA is defined as all of the DNA sequences within a genome that are not found within protein-coding exons, and so are never represented within the amino acid sequence of expressed proteins. By this definition, more than 98% of the human genomes is composed of ncDNA.

Numerous classes of noncoding DNA have been identified, including genes for noncoding RNA (e.g. tRNA and rRNA), pseudogenes, introns, untranslated regions of mRNA, regulatory DNA sequences, repetitive DNA sequences, and sequences related to mobile genetic elements.

Numerous sequences that are included within genes are also defined as noncoding DNA. These include genes for noncoding RNA (e.g. tRNA, rRNA), and untranslated components of protein-coding genes (e.g. introns, and 5' and 3' untranslated regions of mRNA).

Protein-coding sequences (specifically, coding exons) constitute less than 1.5% of the human genome. [14] In addition, about 26% of the human genome is introns. [45] Aside from genes (exons and introns) and known regulatory sequences (8–20%), the human genome contains regions of noncoding DNA. The exact amount of noncoding DNA that plays a role in cell physiology has been hotly debated. Recent analysis by the ENCODE project indicates that 80% of the entire human genome is either transcribed, binds to regulatory proteins, or is associated with some other biochemical activity. [12]

It however remains controversial whether all of this biochemical activity contributes to cell physiology, or whether a substantial portion of this is the result transcriptional and biochemical noise, which must be actively filtered out by the organism. [46] Excluding protein-coding sequences, introns, and regulatory regions, much of the non-coding DNA is composed of: Many DNA sequences that do not play a role in gene expression have important biological functions. Comparative genomics studies indicate that about 5% of the genome contains sequences of noncoding DNA that are highly conserved, sometimes on time-scales representing hundreds of millions of years, implying that these noncoding regions are under strong evolutionary pressure and positive selection. [47]

Many of these sequences regulate the structure of chromosomes by limiting the regions of heterochromatin formation and regulating structural features of the chromosomes, such as the telomeres and centromeres. Other noncoding regions serve as origins of DNA replication. Finally several regions are transcribed into functional noncoding RNA that regulate the expression of protein-coding genes (for example [48] ), mRNA translation and stability (see miRNA), chromatin structure (including histone modifications, for example [49] ), DNA methylation (for example [50] ), DNA recombination (for example [51] ), and cross-regulate other noncoding RNAs (for example [52] ). It is also likely that many transcribed noncoding regions do not serve any role and that this transcription is the product of non-specific RNA Polymerase activity. [46]

Pseudogenes Edit

Pseudogenes are inactive copies of protein-coding genes, often generated by gene duplication, that have become nonfunctional through the accumulation of inactivating mutations. The number of pseudogenes in the human genome is on the order of 13,000, [53] and in some chromosomes is nearly the same as the number of functional protein-coding genes. Gene duplication is a major mechanism through which new genetic material is generated during molecular evolution.

For example, the olfactory receptor gene family is one of the best-documented examples of pseudogenes in the human genome. More than 60 percent of the genes in this family are non-functional pseudogenes in humans. By comparison, only 20 percent of genes in the mouse olfactory receptor gene family are pseudogenes. Research suggests that this is a species-specific characteristic, as the most closely related primates all have proportionally fewer pseudogenes. This genetic discovery helps to explain the less acute sense of smell in humans relative to other mammals. [54]

Genes for noncoding RNA (ncRNA) Edit

Noncoding RNA molecules play many essential roles in cells, especially in the many reactions of protein synthesis and RNA processing. Noncoding RNA include tRNA, ribosomal RNA, microRNA, snRNA and other non-coding RNA genes including about 60,000 long non-coding RNAs (lncRNAs). [12] [55] [56] [57] Although the number of reported lncRNA genes continues to rise and the exact number in the human genome is yet to be defined, many of them are argued to be non-functional. [58]

Many ncRNAs are critical elements in gene regulation and expression. Noncoding RNA also contributes to epigenetics, transcription, RNA splicing, and the translational machinery. The role of RNA in genetic regulation and disease offers a new potential level of unexplored genomic complexity. [59]

Introns and untranslated regions of mRNA Edit

In addition to the ncRNA molecules that are encoded by discrete genes, the initial transcripts of protein coding genes usually contain extensive noncoding sequences, in the form of introns, 5'-untranslated regions (5'-UTR), and 3'-untranslated regions (3'-UTR). Within most protein-coding genes of the human genome, the length of intron sequences is 10- to 100-times the length of exon sequences.

Regulatory DNA sequences Edit

The human genome has many different regulatory sequences which are crucial to controlling gene expression. Conservative estimates indicate that these sequences make up 8% of the genome, [60] however extrapolations from the ENCODE project give that 20 [61] -40% [62] of the genome is gene regulatory sequence. Some types of non-coding DNA are genetic "switches" that do not encode proteins, but do regulate when and where genes are expressed (called enhancers). [63]

Regulatory sequences have been known since the late 1960s. [64] The first identification of regulatory sequences in the human genome relied on recombinant DNA technology. [65] Later with the advent of genomic sequencing, the identification of these sequences could be inferred by evolutionary conservation. The evolutionary branch between the primates and mouse, for example, occurred 70–90 million years ago. [66] So computer comparisons of gene sequences that identify conserved non-coding sequences will be an indication of their importance in duties such as gene regulation. [67]

Other genomes have been sequenced with the same intention of aiding conservation-guided methods, for exampled the pufferfish genome. [68] However, regulatory sequences disappear and re-evolve during evolution at a high rate. [69] [70] [71]

As of 2012, the efforts have shifted toward finding interactions between DNA and regulatory proteins by the technique ChIP-Seq, or gaps where the DNA is not packaged by histones (DNase hypersensitive sites), both of which tell where there are active regulatory sequences in the investigated cell type. [60]

Repetitive DNA sequences Edit

Repetitive DNA sequences comprise approximately 50% of the human genome. [72]

About 8% of the human genome consists of tandem DNA arrays or tandem repeats, low complexity repeat sequences that have multiple adjacent copies (e.g. "CAGCAGCAG. "). [73] The tandem sequences may be of variable lengths, from two nucleotides to tens of nucleotides. These sequences are highly variable, even among closely related individuals, and so are used for genealogical DNA testing and forensic DNA analysis. [74]

Repeated sequences of fewer than ten nucleotides (e.g. the dinucleotide repeat (AC)n) are termed microsatellite sequences. Among the microsatellite sequences, trinucleotide repeats are of particular importance, as sometimes occur within coding regions of genes for proteins and may lead to genetic disorders. For example, Huntington's disease results from an expansion of the trinucleotide repeat (CAG)n within the Huntingtin gene on human chromosome 4. Telomeres (the ends of linear chromosomes) end with a microsatellite hexanucleotide repeat of the sequence (TTAGGG)n.

Tandem repeats of longer sequences (arrays of repeated sequences 10–60 nucleotides long) are termed minisatellites.

Mobile genetic elements (transposons) and their relics Edit

Transposable genetic elements, DNA sequences that can replicate and insert copies of themselves at other locations within a host genome, are an abundant component in the human genome. The most abundant transposon lineage, Alu, has about 50,000 active copies, [75] and can be inserted into intragenic and intergenic regions. [76] One other lineage, LINE-1, has about 100 active copies per genome (the number varies between people). [77] Together with non-functional relics of old transposons, they account for over half of total human DNA. [78] Sometimes called "jumping genes", transposons have played a major role in sculpting the human genome. Some of these sequences represent endogenous retroviruses, DNA copies of viral sequences that have become permanently integrated into the genome and are now passed on to succeeding generations.

Mobile elements within the human genome can be classified into LTR retrotransposons (8.3% of total genome), SINEs (13.1% of total genome) including Alu elements, LINEs (20.4% of total genome), SVAs and Class II DNA transposons (2.9% of total genome).

Human reference genome Edit

With the exception of identical twins, all humans show significant variation in genomic DNA sequences. The human reference genome (HRG) is used as a standard sequence reference.

There are several important points concerning the human reference genome:

  • The HRG is a haploid sequence. Each chromosome is represented once.
  • The HRG is a composite sequence, and does not correspond to any actual human individual.
  • The HRG is periodically updated to correct errors, ambiguities, and unknown "gaps".
  • The HRG in no way represents an "ideal" or "perfect" human individual. It is simply a standardized representation or model that is used for comparative purposes.

The Genome Reference Consortium is responsible for updating the HRG. Version 38 was released in December 2013. [79]

Measuring human genetic variation Edit

Most studies of human genetic variation have focused on single-nucleotide polymorphisms (SNPs), which are substitutions in individual bases along a chromosome. Most analyses estimate that SNPs occur 1 in 1000 base pairs, on average, in the euchromatic human genome, although they do not occur at a uniform density. Thus follows the popular statement that "we are all, regardless of race, genetically 99.9% the same", [80] although this would be somewhat qualified by most geneticists. For example, a much larger fraction of the genome is now thought to be involved in copy number variation. [81] A large-scale collaborative effort to catalog SNP variations in the human genome is being undertaken by the International HapMap Project.

The genomic loci and length of certain types of small repetitive sequences are highly variable from person to person, which is the basis of DNA fingerprinting and DNA paternity testing technologies. The heterochromatic portions of the human genome, which total several hundred million base pairs, are also thought to be quite variable within the human population (they are so repetitive and so long that they cannot be accurately sequenced with current technology). These regions contain few genes, and it is unclear whether any significant phenotypic effect results from typical variation in repeats or heterochromatin.

Most gross genomic mutations in gamete germ cells probably result in inviable embryos however, a number of human diseases are related to large-scale genomic abnormalities. Down syndrome, Turner Syndrome, and a number of other diseases result from nondisjunction of entire chromosomes. Cancer cells frequently have aneuploidy of chromosomes and chromosome arms, although a cause and effect relationship between aneuploidy and cancer has not been established.

Mapping human genomic variation Edit

Whereas a genome sequence lists the order of every DNA base in a genome, a genome map identifies the landmarks. A genome map is less detailed than a genome sequence and aids in navigating around the genome. [82] [83]

An example of a variation map is the HapMap being developed by the International HapMap Project. The HapMap is a haplotype map of the human genome, "which will describe the common patterns of human DNA sequence variation." [84] It catalogs the patterns of small-scale variations in the genome that involve single DNA letters, or bases.

Researchers published the first sequence-based map of large-scale structural variation across the human genome in the journal Nature in May 2008. [85] [86] Large-scale structural variations are differences in the genome among people that range from a few thousand to a few million DNA bases some are gains or losses of stretches of genome sequence and others appear as re-arrangements of stretches of sequence. These variations include differences in the number of copies individuals have of a particular gene, deletions, translocations and inversions.

Structural variation Edit

Structural variation refers to genetic variants that affect larger segments of the human genome, as opposed to point mutations. Often, structural variants (SVs) are defined as variants of 50 base pairs (bp) or greater, such as deletions, duplications, insertions, inversions and other rearrangements. About 90% of structural variants are noncoding deletions but most individuals have more than a thousand such deletions the size of deletions ranges from dozens of base pairs to tens of thousands of bp. [87] On average, individuals carry

3 rare structural variants that alter coding regions, e.g. delete exons. About 2% of individuals carry ultra-rare megabase-scale structural variants, especially rearrangements. That is, millions of base pairs may be inverted within a chromosome ultra-rare means that they are only found in individuals or their family members and thus have arisen very recently. [87]

SNP frequency across the human genome Edit

Single-nucleotide polymorphisms (SNPs) do not occur homogeneously across the human genome. In fact, there is enormous diversity in SNP frequency between genes, reflecting different selective pressures on each gene as well as different mutation and recombination rates across the genome. However, studies on SNPs are biased towards coding regions, the data generated from them are unlikely to reflect the overall distribution of SNPs throughout the genome. Therefore, the SNP Consortium protocol was designed to identify SNPs with no bias towards coding regions and the Consortium's 100,000 SNPs generally reflect sequence diversity across the human chromosomes. The SNP Consortium aims to expand the number of SNPs identified across the genome to 300 000 by the end of the first quarter of 2001. [88]

Changes in non-coding sequence and synonymous changes in coding sequence are generally more common than non-synonymous changes, reflecting greater selective pressure reducing diversity at positions dictating amino acid identity. Transitional changes are more common than transversions, with CpG dinucleotides showing the highest mutation rate, presumably due to deamination.

Personal genomes Edit

A personal genome sequence is a (nearly) complete sequence of the chemical base pairs that make up the DNA of a single person. Because medical treatments have different effects on different people due to genetic variations such as single-nucleotide polymorphisms (SNPs), the analysis of personal genomes may lead to personalized medical treatment based on individual genotypes. [89]

The first personal genome sequence to be determined was that of Craig Venter in 2007. Personal genomes had not been sequenced in the public Human Genome Project to protect the identity of volunteers who provided DNA samples. That sequence was derived from the DNA of several volunteers from a diverse population. [90] However, early in the Venter-led Celera Genomics genome sequencing effort the decision was made to switch from sequencing a composite sample to using DNA from a single individual, later revealed to have been Venter himself. Thus the Celera human genome sequence released in 2000 was largely that of one man. Subsequent replacement of the early composite-derived data and determination of the diploid sequence, representing both sets of chromosomes, rather than a haploid sequence originally reported, allowed the release of the first personal genome. [91] In April 2008, that of James Watson was also completed. In 2009, Stephen Quake published his own genome sequence derived from a sequencer of his own design, the Heliscope. [92] A Stanford team led by Euan Ashley published a framework for the medical interpretation of human genomes implemented on Quake’s genome and made whole genome-informed medical decisions for the first time. [93] That team further extended the approach to the West family, the first family sequenced as part of Illumina’s Personal Genome Sequencing program. [94] Since then hundreds of personal genome sequences have been released, [95] including those of Desmond Tutu, [96] [97] and of a Paleo-Eskimo. [98] In 2012, the whole genome sequences of two family trios among 1092 genomes was made public. [3] In November 2013, a Spanish family made four personal exome datasets (about 1% of the genome) publicly available under a Creative Commons public domain license. [99] [100] The Personal Genome Project (started in 2005) is among the few to make both genome sequences and corresponding medical phenotypes publicly available. [101] [102]

The sequencing of individual genomes further unveiled levels of genetic complexity that had not been appreciated before. Personal genomics helped reveal the significant level of diversity in the human genome attributed not only to SNPs but structural variations as well. However, the application of such knowledge to the treatment of disease and in the medical field is only in its very beginnings. [103] Exome sequencing has become increasingly popular as a tool to aid in diagnosis of genetic disease because the exome contributes only 1% of the genomic sequence but accounts for roughly 85% of mutations that contribute significantly to disease. [104]

Human knockouts Edit

In humans, gene knockouts naturally occur as heterozygous or homozygous loss-of-function gene knockouts. These knockouts are often difficult to distinguish, especially within heterogeneous genetic backgrounds. They are also difficult to find as they occur in low frequencies.

Populations with high rates of consanguinity, such as countries with high rates of first-cousin marriages, display the highest frequencies of homozygous gene knockouts. Such populations include Pakistan, Iceland, and Amish populations. These populations with a high level of parental-relatedness have been subjects of human knock out research which has helped to determine the function of specific genes in humans. By distinguishing specific knockouts, researchers are able to use phenotypic analyses of these individuals to help characterize the gene that has been knocked out.

Knockouts in specific genes can cause genetic diseases, potentially have beneficial effects, or even result in no phenotypic effect at all. However, determining a knockout's phenotypic effect and in humans can be challenging. Challenges to characterizing and clinically interpreting knockouts include difficulty calling of DNA variants, determining disruption of protein function (annotation), and considering the amount of influence mosaicism has on the phenotype. [105]

One major study that investigated human knockouts is the Pakistan Risk of Myocardial Infarction study. It was found that individuals possessing a heterozygous loss-of-function gene knockout for the APOC3 gene had lower triglycerides in the blood after consuming a high fat meal as compared to individuals without the mutation. However, individuals possessing homozygous loss-of-function gene knockouts of the APOC3 gene displayed the lowest level of triglycerides in the blood after the fat load test, as they produce no functional APOC3 protein. [106]

Most aspects of human biology involve both genetic (inherited) and non-genetic (environmental) factors. Some inherited variation influences aspects of our biology that are not medical in nature (height, eye color, ability to taste or smell certain compounds, etc.). Moreover, some genetic disorders only cause disease in combination with the appropriate environmental factors (such as diet). With these caveats, genetic disorders may be described as clinically defined diseases caused by genomic DNA sequence variation. In the most straightforward cases, the disorder can be associated with variation in a single gene. For example, cystic fibrosis is caused by mutations in the CFTR gene and is the most common recessive disorder in caucasian populations with over 1,300 different mutations known. [107]

Disease-causing mutations in specific genes are usually severe in terms of gene function and are fortunately rare, thus genetic disorders are similarly individually rare. However, since there are many genes that can vary to cause genetic disorders, in aggregate they constitute a significant component of known medical conditions, especially in pediatric medicine. Molecularly characterized genetic disorders are those for which the underlying causal gene has been identified. Currently there are approximately 2,200 such disorders annotated in the OMIM database. [107]

Studies of genetic disorders are often performed by means of family-based studies. In some instances, population based approaches are employed, particularly in the case of so-called founder populations such as those in Finland, French-Canada, Utah, Sardinia, etc. Diagnosis and treatment of genetic disorders are usually performed by a geneticist-physician trained in clinical/medical genetics. The results of the Human Genome Project are likely to provide increased availability of genetic testing for gene-related disorders, and eventually improved treatment. Parents can be screened for hereditary conditions and counselled on the consequences, the probability of inheritance, and how to avoid or ameliorate it in their offspring.

There are many different kinds of DNA sequence variation, ranging from complete extra or missing chromosomes down to single nucleotide changes. It is generally presumed that much naturally occurring genetic variation in human populations is phenotypically neutral, i.e., has little or no detectable effect on the physiology of the individual (although there may be fractional differences in fitness defined over evolutionary time frames). Genetic disorders can be caused by any or all known types of sequence variation. To molecularly characterize a new genetic disorder, it is necessary to establish a causal link between a particular genomic sequence variant and the clinical disease under investigation. Such studies constitute the realm of human molecular genetics.

With the advent of the Human Genome and International HapMap Project, it has become feasible to explore subtle genetic influences on many common disease conditions such as diabetes, asthma, migraine, schizophrenia, etc. Although some causal links have been made between genomic sequence variants in particular genes and some of these diseases, often with much publicity in the general media, these are usually not considered to be genetic disorders per se as their causes are complex, involving many different genetic and environmental factors. Thus there may be disagreement in particular cases whether a specific medical condition should be termed a genetic disorder.

Additional genetic disorders of mention are Kallman syndrome and Pfeiffer syndrome (gene FGFR1), Fuchs corneal dystrophy (gene TCF4), Hirschsprung's disease (genes RET and FECH), Bardet-Biedl syndrome 1 (genes CCDC28B and BBS1), Bardet-Biedl syndrome 10 (gene BBS10), and facioscapulohumeral muscular dystrophy type 2 (genes D4Z4 and SMCHD1). [108]

Genome sequencing is now able to narrow the genome down to specific locations to more accurately find mutations that will result in a genetic disorder. Copy number variants (CNVs) and single nucleotide variants (SNVs) are also able to be detected at the same time as genome sequencing with newer sequencing procedures available, called Next Generation Sequencing (NGS). This only analyzes a small portion of the genome, around 1-2%. The results of this sequencing can be used for clinical diagnosis of a genetic condition, including Usher syndrome, retinal disease, hearing impairments, diabetes, epilepsy, Leigh disease, hereditary cancers, neuromuscular diseases, primary immunodeficiencies, severe combined immunodeficiency (SCID), and diseases of the mitochondria. [109] NGS can also be used to identify carriers of diseases before conception. The diseases that can be detected in this sequencing include Tay-Sachs disease, Bloom syndrome, Gaucher disease, Canavan disease, familial dysautonomia, cystic fibrosis, spinal muscular atrophy, and fragile-X syndrome. The Next Genome Sequencing can be narrowed down to specifically look for diseases more prevalent in certain ethnic populations. [110]

1:15000 in American Caucasians

1:176 in Mennonite/Amish communities

Comparative genomics studies of mammalian genomes suggest that approximately 5% of the human genome has been conserved by evolution since the divergence of extant lineages approximately 200 million years ago, containing the vast majority of genes. [111] [112] The published chimpanzee genome differs from that of the human genome by 1.23% in direct sequence comparisons. [113] Around 20% of this figure is accounted for by variation within each species, leaving only

1.06% consistent sequence divergence between humans and chimps at shared genes. [114] This nucleotide by nucleotide difference is dwarfed, however, by the portion of each genome that is not shared, including around 6% of functional genes that are unique to either humans or chimps. [115]

In other words, the considerable observable differences between humans and chimps may be due as much or more to genome level variation in the number, function and expression of genes rather than DNA sequence changes in shared genes. Indeed, even within humans, there has been found to be a previously unappreciated amount of copy number variation (CNV) which can make up as much as 5 – 15% of the human genome. In other words, between humans, there could be +/- 500,000,000 base pairs of DNA, some being active genes, others inactivated, or active at different levels. The full significance of this finding remains to be seen. On average, a typical human protein-coding gene differs from its chimpanzee ortholog by only two amino acid substitutions nearly one third of human genes have exactly the same protein translation as their chimpanzee orthologs. A major difference between the two genomes is human chromosome 2, which is equivalent to a fusion product of chimpanzee chromosomes 12 and 13. [116] (later renamed to chromosomes 2A and 2B, respectively).

Humans have undergone an extraordinary loss of olfactory receptor genes during our recent evolution, which explains our relatively crude sense of smell compared to most other mammals. Evolutionary evidence suggests that the emergence of color vision in humans and several other primate species has diminished the need for the sense of smell. [117]

In September 2016, scientists reported that, based on human DNA genetic studies, all non-Africans in the world today can be traced to a single population that exited Africa between 50,000 and 80,000 years ago. [118]

The human mitochondrial DNA is of tremendous interest to geneticists, since it undoubtedly plays a role in mitochondrial disease. It also sheds light on human evolution for example, analysis of variation in the human mitochondrial genome has led to the postulation of a recent common ancestor for all humans on the maternal line of descent (see Mitochondrial Eve).

Due to the lack of a system for checking for copying errors, [119] mitochondrial DNA (mtDNA) has a more rapid rate of variation than nuclear DNA. This 20-fold higher mutation rate allows mtDNA to be used for more accurate tracing of maternal ancestry. [ citation needed ] Studies of mtDNA in populations have allowed ancient migration paths to be traced, such as the migration of Native Americans from Siberia [120] or Polynesians from southeastern Asia. [ citation needed ] It has also been used to show that there is no trace of Neanderthal DNA in the European gene mixture inherited through purely maternal lineage. [121] Due to the restrictive all or none manner of mtDNA inheritance, this result (no trace of Neanderthal mtDNA) would be likely unless there were a large percentage of Neanderthal ancestry, or there was strong positive selection for that mtDNA. For example, going back 5 generations, only 1 of a person's 32 ancestors contributed to that person's mtDNA, so if one of these 32 was pure Neanderthal an expected

3% of that person's autosomal DNA would be of Neanderthal origin, yet they would have a

97% chance of having no trace of Neanderthal mtDNA. [ citation needed ]

Epigenetics describes a variety of features of the human genome that transcend its primary DNA sequence, such as chromatin packaging, histone modifications and DNA methylation, and which are important in regulating gene expression, genome replication and other cellular processes. Epigenetic markers strengthen and weaken transcription of certain genes but do not affect the actual sequence of DNA nucleotides. DNA methylation is a major form of epigenetic control over gene expression and one of the most highly studied topics in epigenetics. During development, the human DNA methylation profile experiences dramatic changes. In early germ line cells, the genome has very low methylation levels. These low levels generally describe active genes. As development progresses, parental imprinting tags lead to increased methylation activity. [122] [123]

Epigenetic patterns can be identified between tissues within an individual as well as between individuals themselves. Identical genes that have differences only in their epigenetic state are called epialleles. Epialleles can be placed into three categories: those directly determined by an individual's genotype, those influenced by genotype, and those entirely independent of genotype. The epigenome is also influenced significantly by environmental factors. Diet, toxins, and hormones impact the epigenetic state. Studies in dietary manipulation have demonstrated that methyl-deficient diets are associated with hypomethylation of the epigenome. Such studies establish epigenetics as an important interface between the environment and the genome. [124]

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Complete chromosome 8 sequence reveals novel genes and disease risks

Human chromosome 8 sequencing researcher Glennis Logsdon at work in a genome science lab at the University of Washington School of Medicine in Seattle. She led a study published April 7, 2021 in Nature on the structure, function and evolution of the chromosome's complete assembly. Credit: Kendra Hoekzema

The full assembly of human chromosome 8 is reported this week in Nature. While on the outside this chromosome looks typical, being neither short nor long or distinctive, its DNA content and arrangement are of interest in primate and human evolution, in several immune and developmental disorders, and in chromosome sequencing structure and function generally.

This linear assembly is a first for a human autosome—a chromosome not involved in sex determination. The entire sequence of chromosome 8 is 146,259,671 bases. The completed assembly fills in the gap of more than 3 million bases missing from the current reference genome.

The Nature paper is titled "The structure, function and evolution of a complete chromosome 8."

One of several intriguing characteristics of chromosome 8 is a fast-evolving region, where the mutation rate appears to be highly accelerated in humans and human-like species, in contrast to the rest of the human genome.

While chromosome 8 offers some insights into evolution and human biology, the researchers point out that the complete assembly of all human chromosomes would be necessary to acquire a fuller picture.

An international team of scientists collaborated on the chromosome 8 assembly and analysis. The lead author of the paper is Glennis Logsdon, a postdoctoral fellow in genome sciences at the University of Washington School of Medicine in Seattle.

The senior author is Evan Eichler, professor of genome sciences at the UW School of Medicine and a Howard Hughes Medical Institute investigator. His group is noted for developing better methods for sequencing DNA and for analyzing mutational trends that may be important in research on primate evolution and neurological disorders.

In addition to the human chromosome 8 assembly, the project researchers also created high quality draft assemblies of the linking site at the waist of the chromosome, the centromere, in the chimpanzee, orangutan and macaque. The data allowed the scientists to begin to chart the evolutionary history of the chromosome 8 centromere.

Almost like inspecting the depths of a geological site, the researchers observed, on a molecular scale, a layered, mirrored symmetry in how this centromere structure evolved from great ape ancestors. More ancient parts were pushed to the periphery, similar to making room for new material in the middle of a factory production line.

Other research institutions involved in the chromosome 8 assembly project include the Development Therapeutics Branch of the National Cancer Institute, the Genome Informatics Section of the National Human Genome Research Institute, the University of Bari, Italy the Center for Algorithmic Biology at St. Petersburg State University, Russia University of California, San Diego, Washington University in St. Louis, University of Pittsburgh, and the University of California, Santa Cruz. Data were also generated with Oxford Nanopore Technologies and Pacific Biosciences long-read sequencing to resolve gaps in the telomere-to-telomere, or end-to-end, assembly of the chromosome.

Earlier research by a number of scientists had pointed to regions of chromosome 8 as being important both in the normal formation of the brain, as well as to some developmental variations, such as small head size or skull and facial differences. Mutations on this chromosome have also been implicated in some heart defects, certain forms of cancer, premature aging syndromes, immune responses, and immune disorders like psoriasis and Crohn's disease.

However, the full sequencing of this and most other human chromosomes could not be attempted until recently because the technology and methods to wade through large areas of duplication and identical repeats had not become available. Putting together the puzzle accurately from short reads of DNA, for instance, would have been extremely difficult.

The chromosome 8 assembly achievement benefited from advances in long-read technologies, as well as from the availability of DNA material from hydatidiform moles. These are rare, abnormal growths in the placenta.

The full sequencing of chromosome 8 now provides information that might improve, for example, the understanding of what predisposes specific parts of the chromosome's DNA to microdeletions suspected in certain forms of developmental delay, brain and heart malformations, and autoimmune problems.

The researchers were also able to obtain more information on a part of chromosome 8 that contains some of the greatest copy-number variability among people. The repeat unit can vary from 53 to 326 copies.

With the chromosome 8 assembly finished, researchers look forward to the world scientific community completing other human chromosome assemblies, and to new challenges in applying what has been learned to further studies of human genome sequencing.

Genomic DNA

Before discussing the steps a cell undertakes to replicate, a deeper understanding of the structure and function of a cell’s genetic information is necessary. A cell’s complete complement of DNA is called its genome . In prokaryotes, the genome is composed of a single, double-stranded DNA molecule in the form of a loop or circle. The region in the cell containing this genetic material is called a nucleoid. Some prokaryotes also have smaller loops of DNA called plasmids that are not essential for normal growth.

In eukaryotes, the genome comprises several double-stranded, linear DNA molecules (Figure 1) bound with proteins to form complexes called chromosomes. Each species of eukaryote has a characteristic number of chromosomes in the nuclei of its cells. Human body cells (somatic cells) have 46 chromosomes. A somatic cell contains two matched sets of chromosomes, a configuration known as diploid . The letter n is used to represent a single set of chromosomes therefore a diploid organism is designated 2n. Human cells that contain one set of 23 chromosomes are called gametes , or sex cells these eggs and sperm are designated n, or haploid .

Figure 1: There are 23 pairs of homologous chromosomes in a female human somatic cell. These chromosomes are viewed within the nucleus (top), removed from a cell in mitosis (right), and arranged according to length (left) in an arrangement called a karyotype. In this image, the chromosomes were exposed to fluorescent stains to distinguish them. (credit: � Bot”/Wikimedia Commons, National Human Genome Research)

The matched pairs of chromosomes in a diploid organism are called homologous chromosomes . Homologous chromosomes are the same length and have specific nucleotide segments called genes in exactly the same location, or locus . Genes, the functional units of chromosomes, determine specific characteristics by coding for specific proteins. Traits are the different forms of a characteristic. For example, the shape of earlobes is a characteristic with traits of free or attached.

Each copy of the homologous pair of chromosomes originates from a different parent therefore, the copies of each of the genes themselves may not be identical. The variation of individuals within a species is caused by the specific combination of the genes inherited from both parents. For example, there are three possible gene sequences on the human chromosome that codes for blood type: sequence A, sequence B, and sequence O. Because all diploid human cells have two copies of the chromosome that determines blood type, the blood type (the trait) is determined by which two versions of the marker gene are inherited. It is possible to have two copies of the same gene sequence, one on each homologous chromosome (for example, AA, BB, or OO), or two different sequences, such as AB.

Minor variations in traits such as those for blood type, eye color, and height contribute to the natural variation found within a species. The sex chromosomes, X and Y, are the single exception to the rule of homologous chromosomes other than a small amount of homology that is necessary to reliably produce gametes, the genes found on the X and Y chromosomes are not the same.

Genomic DNA

Before discussing the steps a cell undertakes to replicate, a deeper understanding of the structure and function of a cell’s genetic information is necessary. A cell’s complete complement of DNA is called its genome. In prokaryotes, the genome is composed of a single, double-stranded DNA molecule in the form of a loop or circle. The region in the cell containing this genetic material is called a nucleoid. Some prokaryotes also have smaller loops of DNA called plasmids that are not essential for normal growth.

Figure 1. There are 23 pairs of homologous chromosomes in a female human somatic cell. These chromosomes are viewed within the nucleus (top), removed from a cell in mitosis (right), and arranged according to length (left) in an arrangement called a karyotype. In this image, the chromosomes were exposed to fluorescent stains to distinguish them. (credit: “718 Bot”/Wikimedia Commons, National Human Genome Research)

In eukaryotes, the genome comprises several double-stranded, linear DNA molecules (Figure 1) bound with proteins to form complexes called chromosomes. Each species of eukaryote has a characteristic number of chromosomes in the nuclei of its cells. Human body cells (somatic cells) have 46 chromosomes. A somatic cell contains two matched sets of chromosomes, a configuration known as diploid. The letter n is used to represent a single set of chromosomes therefore a diploid organism is designated 2n. Human cells that contain one set of 23 chromosomes are called gametes, or sex cells these eggs and sperm are designated n, or haploid.

The matched pairs of chromosomes in a diploid organism are called homologous chromosomes. Homologous chromosomes are the same length and have specific nucleotide segments called genes in exactly the same location, or locus. Genes, the functional units of chromosomes, determine specific characteristics by coding for specific proteins. Traits are the different forms of a characteristic. For example, the shape of earlobes is a characteristic with traits of free or attached.

Each copy of the homologous pair of chromosomes originates from a different parent therefore, the copies of each of the genes themselves may not be identical. The variation of individuals within a species is caused by the specific combination of the genes inherited from both parents. For example, there are three possible gene sequences on the human chromosome that codes for blood type: sequence A, sequence B, and sequence O. Because all diploid human cells have two copies of the chromosome that determines blood type, the blood type (the trait) is determined by which two versions of the marker gene are inherited. It is possible to have two copies of the same gene sequence, one on each homologous chromosome (for example, AA, BB, or OO), or two different sequences, such as AB.

Minor variations in traits such as those for blood type, eye color, and height contribute to the natural variation found within a species. The sex chromosomes, X and Y, are the single exception to the rule of homologous chromosomes other than a small amount of homology that is necessary to reliably produce gametes, the genes found on the X and Y chromosomes are not the same.

The Human Genome

What makes each one of us unique? You could argue that the environment plays a role, and it does to some extent. But most would agree that your parents have something to do with your uniqueness. In fact, it is our genes that make each one of us unique &ndash or at least genetically unique. We all have the genes that make us human: the genes for skin and bones, eyes and ears, fingers and toes, and so on. However, we all have different skin colors, different bone sizes, different eye colors and different ear shapes. In fact, even though we have the same genes, the products of these genes work a little differently in most of us. And that is what makes us unique.

The human genome is the genome - all the DNA - of Homo sapiens. Humans have about 3 billion bases of information, divided into roughly 20,000 to 22,000 genes, which are spread among non-coding sequences and distributed among 24 distinct chromosomes (22autosomes plus the X and Y sex chromosomes) (below). The genome is all of the hereditary information encoded in the DNA, including the genes and non-coding sequences.

Human Genome, Chromosomes, and Genes. Each chromosome of the human genome contains many genes as well as noncoding intergenic (between genes) regions. Each pair of chromosomes is shown here in a different color.

Thanks to the Human Genome Project, scientists now know the DNA sequence of the entire human genome. The Human Genome Project is an international project that includes scientists from around the world. It began in 1990, and by 2003, scientists had sequenced all 3 billion base pairs of human DNA. Now they are trying to identify all the genes in the sequence. The Human Genome Project has produced a reference sequence of the human genome. The human genome consists of protein-coding exons, associated introns and regulatory sequences, genes that encode other RNA molecules, and other DNA sequences (sometimes referred to as "junk" DNA), which are regions in which no function as yet been identified.

You can watch a video about the Human Genome Project and how it cracked the "code of life" at this link:

Our Molecular Selves video discusses the human genome, and is available at or, Unlocking Life's Code is the Smithsonian's National Museum of Natural History exhibit of the human genome. See to visit the exhibit.

ENCODE: The Encyclopedia of DNA Elements

In September 2012, ENCODE, The Encyclopedia of DNA Elements, was announced. ENCODE was a colossal project, involving over 440 scientists in 32 labs the world-over, whose goal was to understand the human genome. It had been thought that about 80% of the human genome was "junk" DNA. ENCODE has established that this is not true. Now it is thought that about 80% of the genome is active. In fact, much of the human genome is regulatory sequences, on/off switches that tell our genes what to do and when to do it. Dr. Eric Green, director of the National Human Genome Research Institute of the National Institutes of Health which organized this project, states, "It's this incredible choreography going on, of a modest number of genes and an immense number of . switches that are choreographing how those genes are used."

It is now thought that at least three-quarters of the genome is involved in making RNA, and most of this RNA appears to help regulate gene activity. Scientists have also identified about 4 million sites where proteins bind to DNA and act in a regulatory capacity. These new findings demonstrate that the human genome has remarkable and precise, and complex, controls over the expression of genetic information within a cell.

The Human Genome Is—Finally!—Complete

The Human Genome Project left 8 percent of our DNA unexplored. Now, for the first time, those enigmatic regions have been revealed.

When the human genome was first deemed “complete” in 2000, the news was met with great international fanfare. The two rival groups vying to finish the genome first—one a large government-led consortium, the other an underdog private company—agreed to declare joint success. They shook hands at the White House. Bill Clinton presided. Tony Blair beamed in from London. “We are standing at an extraordinary moment in scientific history,” one prominent scientist declared when those genomes were published. “It’s as though we have climbed to the top of the Himalayas.”

But actually, the human genome was not complete. Neither group had reached the real summit. As even the contemporary coverage acknowledged, that version was more of a rough draft, riddled with long stretches where the DNA sequence was still fuzzy or missing. The private company soon pivoted and ended its human-genome project, though scientists with the public consortium soldiered on. In 2003, with less glitz but still plenty of headlines, the human genome was declared complete once again.

But actually, the human genome was still not complete. Even the revised draft was missing about 8 percent of the genome. These were the hardest-to-sequence regions, full of repeating letters that were simply impossible to read with the technology at the time.

Finally, this May, a separate group of scientists quietly posted a preprint online describing what can be deemed the first truly complete human genome—a readout of all 3.055 billion letters across 23 human chromosomes. The group, led by relatively young researchers, came together on Slack from around the world to finish the task abandoned 20 years ago. There was no splashy White House announcement this time, no talk of summiting the Himalayas the paper itself is still under review for official publication in a journal. But the lack of pomp belies what an achievement this is: To complete the human genome, these scientists had to figure out how to map its most mysterious and neglected repeating regions, which may now finally get their scientific due.

“I consider this a landmark,” says Steven Henikoff, a molecular biologist at Fred Hutchinson Cancer Research Center, who was not involved in the project. Henikoff studies one of those enigmatic, hard-to-sequence regions where previous human-genome projects had given up: centromeres, which are the slightly pinched middles of each chromosome. Chromosomes, of which humans have 23 pairs, each consist of a long, continuous stretch of DNA that can be condensed into a rod shape the DNA at the centromere is particularly dense.

On five human chromosomes, the centromere is not in the middle but very close to one end, dividing the chromosome into one long and one very short arm. These short arms are also full of repeats that had never been entirely sequenced until now. Centromeres, short arms, and other types of repeating regions made up most of the 238 million letters the consortium ultimately added or corrected in the human genome.

The repeat-rich segments of the human genome do not usually contain genes, which is one reason they’ve long been neglected. Geneticists have focused largely on genes because their function is obvious and simple: A gene encodes a protein. (One big surprise of the earlier drafts of the human genome is how little of our DNA actually encodes proteins—only 1 percent. The role of the remaining 99 percent is becoming clearer.) Indeed, there have been hints that these repeat-rich regions also play important roles in how genes get expressed and passed on, and anomalies in them have been linked to cancer and aging. The consortium found 79 new genes hidden among the repeats too. With a map of these repeating regions finally in hand, scientists can probe more carefully their function.

The effort to finish the genome was “entirely grassroots,” says Adam Phillippy, a computational geneticist at the National Institutes of Health who co-leads the Telomere-to-Telomere (T2T) consortium that completed the genome. (Telomeres are the regions at the ends of chromosomes, so telomere to telomere means “end to end.”) Phillippy and Karen Miga, a geneticist at UC Santa Cruz, decided to create the consortium in 2018, after a call when they realized that they both harbored ambitions of finishing the human genome.

“I’m in love with repeats,” says Miga, who came to the project as a biologist trying to understand what those repeats do. Phillippy, a computer scientist by training, brought technical chops. Traditional sequencing technologies fragment DNA into small pieces, and computer algorithms have to reassemble them like puzzle pieces. The problem is that the pieces from repeating regions all look nearly the same. Now two new “long-read” sequencing technologies—called PacBio HiFi and Oxford Nanopore—allow scientists to read longer stretches of the genome. These sequencers still can’t handle chunks big enough to cross an entire centromere or a short arm, but at least the algorithms have larger puzzle pieces to assemble.

The role of centromere sequences, like many other repeating regions, is not yet fully understood, but they are most classically known as the key to cell division. When a cell divides in two, a protein spindle attaches to the centromeres, yanking the chromosomes apart to make sure that each cell gets the right number. When this goes wrong in eggs or sperm, babies can be born with chromosomal anomalies such as Down syndrome or Turner syndrome. When it goes wrong in other parts of the body, we can end up with blood cells, for example, that have too many or too few chromosomes. This is a hallmark of aging: It’s not unusual for men older than 70 to have lost the Y chromosomes in their blood cells. In one of two companion papers uploaded alongside the complete genome, the T2T consortium showed that Oxford Nanopore’s long-read technology can also be used to map where exactly the protein spindle attaches to the centromere. Examining the sequences in those regions might yield new clues to chromosomal anomalies.

The repeat-rich short arms of the chromosomes are similarly mysterious. They definitely play some role in the cellular machinery that translates genes into proteins, and knowing their sequences could shed more light on that function. Brian McStay, a biologist at the National University of Ireland at Galway, likens the complete genome to a “parts list” for chromosomes that allows scientists to try taking out the building blocks one by one. “Knowing what this parts list is, we can say, ‘This is exactly what our chromosome looks like,’” McStay says. “‘Let’s delete this and see what the impact on the function of that chromosome is.’”

As impressive as the technical feat of sequencing a complete human genome is, scientists told me that one genome is only one snapshot. Seeing how these repeating regions change over time from person to person, species to species, will be far more interesting. “What happens in cancer? What happens in development? What happens if you compare offspring to parents?” Henikoff says. The consortium proved that these repeating regions are sequenceable with the new long-read technologies. Now they can be applied to more genomes, allowing scientists to compare one with another.

Indeed, Miga says that the ultimate dream is to make every genome that scientists attempt to sequence complete from end to end, telomere to telomere. But first, the group has a more immediate goal in mind. If you wanted to fault the new genome for not being “complete,” you could point to the fact that it comprises only a single set of 23 chromosomes, whereas normal human cells have 23 pairs. To simplify the task, the group used cells from a particular type of tumor that develops from an abnormal fertilized egg and ends up with just 23 single chromosomes. The team will have to use different cells, with 23 pairs of chromosomes, to complete what is known as a “diploid” genome.

“The next major milestone would be routine diploid genomes,” says Shilpa Garg, a geneticist at the University of Copenhagen, in Denmark. Garg has used PacBio HiFi to rapidly assemble human genomes—minus some tricky regions such as the centromeres—at a rate of a few per day. That speed could help in clinical settings too, by making it easier for doctors to more regularly diagnose patients using genome sequencing. (In comparison, she says, assembling genomes from older sequencing technology takes as long as three weeks.) Truly complete genome sequencing, repeating regions and all, is getting easier and faster. Soon, another complete human genome will not be news at all.

The Human Genome at 20: How Biology’s Most-Hyped Breakthrough Led to Anticlimax and Arrests

When President Bill Clinton took to a White House lectern 20 years ago to announce that the human genome sequence had been completed, he hailed the breakthrough as “the most important, most wondrous map ever produced by humankind.” The scientific achievement was placed on par with the moon landings.

It was hoped that having access to the sequence would transform our understanding of human disease within 20 years, leading to better treatment, detection, and prevention. The famous journal article that shared our genetic ingredients with the world, published in February 2001, was welcomed as a “Book of Life” that could revolutionize medicine by showing which of our genes led to which illnesses.

But in the two decades since, the sequence has underwhelmed. The potential of our newfound genetic self-knowledge has not been fulfilled. Instead, what has emerged is a new frontier in genetic research: new questions for a new batch of researchers to answer.

Today, the gaps between our genes, and the switches that direct genetic activity, are emerging as powerful determinants behind how we look and how we get ill – perhaps deciding up to 90% of what makes us different from one another. Understanding this “genetic dark matter,” using the knowledge provided by the human genome sequence, will help us to push further into our species’ genetic secrets.

The announcement was first made in a joint press conference between President Bill Clinton and Prime Minister Tony Blair in 2000.

Unraveled code

Cracking the human genetic code took 13 years, US$2.7 billion (£1.9 billion) and hundreds of scientists peering through over 3 billion base pairs in our DNA. Once mapped, our genetic data helped projects like the Cancer Dependency Map and the Genome Wide Association Studies better understand the diseases that afflict humans.

But some results were disappointing. Back in 2000, as it was becoming clear the genome sequence was imminent, the genomics community began excitedly placing bets predicting how many genes the human genome would contain. Some bets were as high as 300,000, others as low as 40,000. For context, the onion genome contains 60,000 genes.

Dispiritingly, it turned out that our genome contains roughly the same number of genes as a mouse or a fruit fly (around 21,000), and three times less than an onion. Few would argue that humans are three times less complex than an onion. Instead, this discovery suggested that the number of genes in our genome had little to do with our complexity or our difference from other species, as had been previously assumed.

Great responsibility

Access to the human genome sequence also presented the scientific community with a huge number of important ethical questions, underscored in 2000 by Prime Minister Tony Blair when he cautioned: “With the power of this discovery comes the responsibility to use it wisely.”

Ethicists were particularly concerned about questions of “genetic discrimination,” like whether our genes could be used against us as evidence in a court of law, or as a basis for exclusion: a new kind of twisted hierarchy determined by our biology.

Some of these concerns were addressed by legislation against genetic discrimination, like the US Genetic Information Nondiscrimination Act of 2008. Other concerns, like those around so-called “designer babies,” are still being put to the test today.

In 2018, human embryos were gene edited by a Chinese scientist, using a method called CRISPR which allows targeted sections of DNA to be snipped off and replaced with others. The scientist involved was subsequently jailed, suggesting that there remains little appetite for human genetic experimentation.

On the other hand, to deny available genetic treatments to willing patients may one day be considered unethical – just as some countries have chosen to legalize euthanasia on ethical grounds. Questions remain about how humanity should handle its genetic data.

The Chinese scientist He Jiankui announced in 2018 that he had created gene-edited twins. He was jailed in 2019.

Disease diversions

With human gene editing still highly contentious, researchers have instead looked to find out which genes may be responsible for humanity’s illnesses. Yet when scientists investigated which genes are linked to human diseases, they were met with a surprise. After comparing huge samples of human DNA to find whether certain genes led to certain illnesses, they found that many unexpected sections of the genome were involved in the development of human disease.

The genome contains two sections: the coding genome, and the non-coding genome. The coding genome represents just 1.7% of our DNA, but is responsible for coding the proteins that are the essential building blocks of life. Genes are defined by their ability to code proteins: so 1.7% of our genome consists of genes.

The non-coding genome, which makes up the remaining 98.3% of our DNA, doesn’t code proteins. This largely unknown section of the genome was once dismissed as “junk DNA,” previously thought to be useless. It contained no protein-creating genes, so it was assumed the non-coding genome had little to do with the stuff of life.

Bewilderingly, scientists found that the non-coding genome was actually responsible for the majority of information that impacted disease development in humans. Such findings have made it clear that the non-coding genome is actually far more important than previously thought.

Enhanced capabilities

Within this non-coding part of the genome, researchers have subsequently found short regions of DNA called enhancers: gene switches that turn genes on and off in different tissues at different times. They found that enhancers needed to shape the embryo have changed very little during evolution, suggesting that they represent a major and important source of genetic information.

These studies inspired one of us, Alasdair, to explore the possible role of enhancers in behaviors such as alcohol intake, anxiety, and fat intake. By comparing the genomes of mice, birds, and humans we identified an enhancer that has changed relatively little over 350 million years – suggesting its importance in species’ survival.

When we used CRISPR genome editing to delete this enhancer from the mouse genome, those mice ate less fat, drank less alcohol, and displayed reduced anxiety. While these may all sound like positive changes, it’s likely that these enhancers evolved in calorically poor environments full of predators and threats. At the time, eating high-calorie food sources such as fat and fermented fruit, and being hyper-vigilant of predators, would have been key for survival. However, in modern society these same behaviors may now contribute to obesity, alcohol abuse, and chronic anxiety.

Intriguingly, subsequent genetic analysis of a major human population cohort has shown that changes in the same human enhancer were also associated with differences in alcohol intake and mood. These studies demonstrate that enhancers are not only important for normal physiology and health, but that changing them could result in changes in behavior that have major implications for human health.

Given these new avenues of research, we appear to be at a crossroads in genetic biology. The importance of gene enhancers in health and disease sits uncomfortably with our relative inability to identify and understand them.

And so in order to make the most of the sequencing of the human genome two decades ago, it’s clear that research must now look beyond the 1.7% of the genome that encodes proteins. In exploring uncharted genetic territory, like that represented by enhancers, biology may well locate the next swathe of healthcare breakthroughs.

NHGRI researchers generate complete human X chromosome sequence

This accomplishment opens a new era in genomics research.

Researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), have produced the first end-to-end DNA sequence of a human chromosome. The results, published today in the journal Nature, show that generating a precise, base-by-base sequence of a human chromosome is now possible, and will enable researchers to produce a complete sequence of the human genome.

“This accomplishment begins a new era in genomics research,” said Eric Green, M.D., Ph.D., NHGRI director. “The ability to generate truly complete sequences of chromosomes and genomes is a technical feat that will help us gain a comprehensive understanding of genome function and inform the use of genomic information in medical care.”

After nearly two decades of improvements, the reference sequence of the human genome is the most accurate and complete vertebrate genome sequence ever produced. However, there are hundreds of gaps or missing DNA sequences that are unknown.

These gaps most often contain repetitive DNA segments that are exceptionally difficult to sequence. Yet, these repetitive segments include genes and other functional elements that may be relevant to human health and disease.

Because a human genome is incredibly long, consisting of about 6 billion bases, DNA sequencing machines cannot read all the bases at once. Instead, researchers chop the genome into smaller pieces, then analyze each piece to yield sequences of a few hundred bases at a time. Those shorter DNA sequences must then be put back together.

Senior author Adam Phillippy, Ph.D., at National Human Genome Research Institute (NHGRI) compared this issue to solving a puzzle.

“Imagine having to reconstruct a jigsaw puzzle. If you are working with smaller pieces, each contains less context for figuring out where it came from, especially in parts of the puzzle without any unique clues, like a blue sky,” he said. “The same is true for sequencing the human genome. Until now, the pieces were too small, and there was no way to put the hardest parts of the genome puzzle together.”

Imagine having to reconstruct a jigsaw puzzle. If you are working with smaller pieces, each contains less context for figuring out where it came from, especially in parts of the puzzle without any unique clues, like a blue sky. The same is true for sequencing the human genome. Until now, the pieces were too small, and there was no way to put the hardest parts of the genome puzzle together.

Of the 24 human chromosomes (including X and Y), study authors Phillippy and Karen Miga, Ph.D., at the University of California, Santa Cruz, chose to complete the X chromosome sequence first, due to its link with a myriad of diseases, including hemophilia, chronic granulomatous disease and Duchenne muscular dystrophy.

Humans have two sets of chromosomes, one set from each parent. For example, biologically female humans inherit two X chromosomes, one from their mother and one from their father. However, those two X chromosomes are not identical and will contain many differences in their DNA sequences.

In this study, researchers did not sequence the X chromosome from a normal human cell. Instead, they used a special cell type – one that has two identical X chromosomes. Such a cell provides more DNA for sequencing than a male cell, which has only a single copy of an X chromosome. It also avoids sequence differences encountered when analyzing two X chromosomes of a typical female cell.

The authors and their colleagues capitalized on new technologies that can sequence long segments of DNA. Instead of preparing and analyzing small pieces of DNA, they used a method that leaves DNA molecules largely intact. These large DNA molecules were then analyzed by two different instruments. Each of them generates very long DNA sequences – something previous instruments could not accomplish.

After analyzing the human X chromosome in this fashion, Phillippy and his team used their newly developed computer program to assemble the many segments of generated sequences. Miga’s group led the effort to close the largest remaining sequence gap on the X chromosome, the roughly 3 million bases of repetitive DNA found at the middle portion of the chromosome, called the centromere.

Animation depicting the puzzle pieces of DNA sequences coming together. Credit: Ernesto Del Aguila III, NHGRI.

There is no “gold standard” for researchers to critically evaluate the accuracy of assembling such highly repetitive DNA sequences. To help confirm the validity of the generated sequence, Miga and her collaborators performed several validation steps.

“We have never actually seen these sequences before in our genome, and do not have many tools to test if the predictions we are making are correct. This is why it is important to have specialists in the genomics community weigh in and ensure the final product is high-quality,” Miga said.

The effort is part of a broader initiative by the Telomere-to-Telomere (T2T) consortium, partially funded by NHGRI. The consortium aims to generate a complete reference sequence of the human genome.

The T2T consortium is continuing its efforts with the remaining human chromosomes, aiming to generate a complete human genome sequence in 2020.

“We don’t yet know what we’ll find in the newly uncovered sequences. It is the exciting unknown of discovery. This is the era of complete genome sequences, and we are embracing it wholeheartedly,” Phillippy said.

Potential challenges remain. Chromosomes 1 and 9, for example, have repetitive DNA segments that are much larger than the ones encountered on the X chromosome.

“We know these previously uncharted sites in our genome are very different among individuals, but it is important to start figuring out how these differences contribute to human biology and disease,” Miga said. Both Phillippy and Miga agree that enhancing sequencing methods will continue to create new opportunities in human genetics and genomics.


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