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How it is determined that a particular gene or set of genes is responsible for a trait? Is it just a statistical analysis of people showing and not showing the trait and the genes they have (or don't have) and their variants (alleles)? Or, there is something more.
In the below list of technics, I am assuming we are talking about haploid individuals (to avoid discussion about dominance relationship) and assuming no epistasis but the technics can 'easily' be extended to include these cases. I also assume we are talking about coding regions.
Note that I am more of a biostatistician / population geneticist than a molecular geneticist, so I am pretty sure I will unwillingly bias my list toward what I know most. There is a lot to say about every single technic but of course, this cannot be covered in a single StackExchange post.
Statistical association (observational study) with existing variance in natural population. Do carrier of a given allele have another trait value than the carrier of the other allele. Possible confounding variables include population structure and linkage disequilibrium.
- Population structure: To deal with this confounding variable, we can make a genetic PCA and include the first two axes as covariate in a type I sum of squares regression. We can also use tools such as STRUCTURE to infer the population structure and then use the inferred groups as a nominal covariate.
- Linkage disequilibrium: We typically consider a number of marker that we try to associate to a specific phenotypic trait. It is impossible to tell whether the observed association is directly caused by the marker we observe or by a tightly linked marker. For further investigations below technics must be considered.
Statistical association (experimental study). It is possible to create the treatment groups by knocking out (or other technics such as the now popular CRISPR technic) specific gene in out in some individuals and look for a statistical association. The advantage of such manipulation is that we can create the optimal level of genetic variance we need to increase our statistical power.
Transcriptome analysis. Making sure the coding region is being expressed in the tissue of interest. E.g. if you expect a given gene to affect myosin tertiary structure, you might want to make sure the coding region is indeed expressed in the muscles and not only in the brain!
Protein action. It is also possible to study the specific action of the protein coded by the coding region of interest. Such studies typically require the study of an entire biological pathway and is often demanding and quite expensive. Here the methodology are diverse but they're discussion is both outside the scope of the question and outside the scope of my knowledge.
Example - Genetic Basis of Color Adaptation in mice
In a comment, you asked
Is there any research paper, review paper or blog which covers entire details how the association and mechanism was established for any of those discoveries?
In most study cases, not all of the above steps are being considered. Also, even if it is the case, such study will be covered by several peer-reviewed papers and not a single one. I don't know of any peer-review paper that explains the whole process for a particular case but those probably exist.
There are documents that explain such process for layman. For example From Darwin to DNA: The Genetic Basis of Color Adaptations by Hoekstra is a standard reading for undergraduate that will interest you. It is easy and pleasant to read. Quoting from this article
In this essay, we will take a journey - into the laboratory and the field - to understand the genetic basis of adaptation in natural populations of mice, and the phenotype we will focus on is the color of their fur.
The gene of interest in this paper is melanocortin-1 receptor (Mc1r). Depending on what level of understanding you want to reach, the article might be a bit too introductory but it refers to some good peer review papers that will allow you to further your knowledge.
Is intelligence determined by genetics?
Like most aspects of human behavior and cognition, intelligence is a complex trait that is influenced by both genetic and environmental factors.
Intelligence is challenging to study, in part because it can be defined and measured in different ways. Most definitions of intelligence include the ability to learn from experiences and adapt to changing environments. Elements of intelligence include the ability to reason, plan, solve problems, think abstractly, and understand complex ideas. Many studies rely on a measure of intelligence called the intelligence quotient (IQ).
Researchers have conducted many studies to look for genes that influence intelligence. Many of these studies have focused on similarities and differences in IQ within families, particularly looking at adopted children and twins. These studies suggest that genetic factors underlie about 50 percent of the difference in intelligence among individuals. Other studies have examined variations across the entire genomes of many people (an approach called genome-wide association studies or GWAS) to determine whether any specific areas of the genome are associated with IQ. These studies have not conclusively identified any genes that have major roles in differences in intelligence. It is likely that a large number of genes are involved, each of which makes only a small contribution to a person’s intelligence.
Intelligence is also strongly influenced by the environment. Factors related to a child’s home environment and parenting, education and availability of learning resources, and nutrition, among others, all contribute to intelligence. A person’s environment and genes influence each other, and it can be challenging to tease apart the effects of the environment from those of genetics. For example, if a child’s IQ is similar to that of his or her parents, is that similarity due to genetic factors passed down from parent to child, to shared environmental factors, or (most likely) to a combination of both? It is clear that both environmental and genetic factors play a part in determining intelligence.
Of course, genetic predisposition cannot be excluded from the complex of causes causing crime: it may even be decisive. But every individual must have a sober mind. If he has it, then the criminal environment will never become a native element. If a sober mind is absent, then the person will float at the will of those genes that dominate him, and only God knows where it goes.
Tags: criminality, cruelty, genes, genetic predisposition to disease, genetics, hereditary, heredity
Segregation Patterns Indicate Whether Mutations Are on the Same or Different Chromosomes
As discussed earlier, during meiosis each chromosome segregates independently. Therefore, traits controlled by genes on separate chromosomes also segregate independently (Figure 8-15). The observation that two mutant traits segregate independently indicates that the mutations are located on different chromosomes. Conversely, mutant gene loci that segregate together at a higher frequency than predicted by random assortment of chromosomes indicate that these loci are on the same chromosome such loci are referred to as linked. Recombination between loci on the same chromosome provides a basis for mapping them relative to each other along the length of the chromosome, as discussed below.
When Mendel crossed strains of peas that were pure (homozygous) for each of two traits — say, round (R/R) and yellow (Y/Y) peas with wrinkled (r/r) and green (y/y) peas — the plants of the F2 generation (more. )
Gene: Introduction, Concepts and Structure | Cell Biology
Mendel’s, (1865) experiments with Garden pea plant showed that certain hereditary “factors” were concerned in determining the appear­ance of certain morphological traits.
Such Mendelian “factors” were described as “gene” by Johanssen (1909) and these genes were shown to be present on chromosome as beads on string and this was the basis of the chromosome theory of heredity proposed (1902-1903) by Shutton and Boveri.
Thus on the basis of these classical observations, a gene was considered in the early days as a single, small and indivisible hereditary unit that occurred at a definite point on the chromosome and was responsible for a specific phenotypic character. As the knowledge of gene increased day by day in the subsequent studies, the classical concept about gene was changed and modified accordingly.
The Changing Concept of Gene:
The discovery of many phenomena like crossing over, gene-recombination and gene mutation have provided another set of information about gene. But recombination was not believed to occur only between the beads or genes.
Hence the gene was not considered sub-divisible. Thus a gene is considered to control the inheritance of one character, to be indivisible by recombination and to be the smallest unit capable of mutation.
It was soon realised that a gene, in true sense, is not responsible for the expression of one trait by itself, although it may exercise the major control on its development.
That genes express themselves through synthe­sis of enzyme was demonstrated for the first time in 1941 by G. W. Beadle and E. L. Tatum due to their discovery of biochemical mutations in Neurospora. Based on their work, Beadle and Tatum proposed a concept called “one gene-one enzyme” hypothesis.
Thus it became evident that a gene controlled a biochemical reaction by directing the production of a single enzyme. But it was also realised that one gene produces a single polypeptide and not one enzyme as the latter may consist of more than one polypeptide. Thus, the gene may now be defined as a segment of DNA which contains the information for a single polypeptide (the functional unit).
Each functional unit consists of a series of nucleotides that specifies the sequence of amino acid residue of polypeptide chain such as those of the A and B chains of the tryptophan synthetase enzyme or the α and β chains of haemoglobin. But it is shown that a change in as little as one nucleotide of the polypeptide specifying gene may mutate and produce a variant of the wild type chain that differs in one amino acid residue.
So the functional gene or unit is not the same as the mutational gene, but appears to consist of many mutable sites. The gene must also be considered from the standpoint of the nature of the sites of which recombination may occur.
The functional gene, therefore, appears to be composed of many mutational as well as re-combinational sub-units. The first evidence that the gene was sub-divisible by mutation and recombination came from studies of the X- linked lozenge locus of Drosophila melanogaster by C.P. Oliver in 1940.
Oliver demonstrated that crossing over oc­curred between two mutants such as alleles lzs and Izg of the sex linked lozenge locus of D. melanogaster at a low frequency of 0.2%. This was the first evidence for intragenic recom­bination.
According to classical concept a gene is not sub-divisible in that crossing over does not occur within a gene it always occurs between two separate genes. But Oliver’s studies first indicated that the gene was, in fact, more complex than a bead on a string.
They were first steps towards the present concept of the gene as a long sequence of nucleotide pairs that is capable of mutating and recombining at many different sites along its length.
(i) Cis-Trans Test:
This is an indirect experimental evidence to prove that a gene is sub-divisible. The standard phenotype, i.e., parental form, without any mutation, is called wild type. The genes present in the wild type organism is generally designated by ‘+’ sign for comparison with mutant gene.
Before going to discuss the cis-trans test, it is reasonable to understand the meaning of cis and trans arrangement of gene. Cis arrangement means the condition in which a double heterozygote has received two linked mutations from one parent and their wild type alleles from the other parent, e.g., ab/ab x ++/.++-produces heterozygotes ab/++ (Fig. 15.1).
Trans arrangement means the condition in which a double heterozygote has received a mu­tant and a wild type allele from each parent— for example a+/a+x+b/-l-b produces a+/+b (Fig. 15.2).
In a cis-trans test the phenotypes produced in cis and trans heterozygotes for two mutant alleles are compared with each other. In a cis heterozygote, both mutant alleles are located in the same chromosome and their wild type alle­les are present in the homologous chromosome, i.e., mutant alleles are linked in the coupling phase.
Thus it is expected to produce the wild type phenotype (unless the mutant alleles are dominant or co-dominant) irrespective of whether the two mutant, alleles are located in the same gene or in two different genes.
On the other hand, in case of trans heterozygotes one, mutant alleles are located in the homologous chromosome—they are linked in the repulsion phase. Hence, in trans heterozygotes, it is expected to produce the mutant phenotype if the two alleles are located in the same gene. But if they are located in two different genes, the wild type phenotype would be produced.
Hence simply by comparing the phenotypes for any two mutant alleles it is possible to determine if they are located in the same gene or in two different genes.
They are located in the same gene if their cis heterozygotes produce the wild type phenotype, while their trans heterozygotes have the mutant phenotype. But if both their cis and trans-heterozygotes have the wild type phenotype they are considered to be located in two different genes.
(ii) Complementation Test:
The production of wild type phenotype in a trans-heterozygote for two mutant alleles is termed as complementation and such a study is known as complementation test. The results obtained from complementation tests are highly precise and reliable and they permit an oper­ational demarcation of gene.
Mutant alleles present in the same gene do not show com­plementation, while those located in different genes show complementation. Actually, this concept is generally true in prokaryotes but in eukaryotes several noteworthy exceptions are known.
The basis of complementation test (Fig. 15.3) may be simply described as follows. A gene produces its effect primarily by directing the production of an active enzyme or polypeptide. On the other hand, a mutant allele of this gene directs the production of an inactive form of the enzyme as a result of which it produces the mutant phenotype.
In the cis heterozygote, one of the two homologous chromosomes has the wild type allele(s) of the gene(s). This wild type allele will direct the synthesis of active enzyme—thereby producing the wild type phe­notype.
In trans heterozygotes, if the mutant alleles are present in the same gene, the enzyme molecules produced by them will be inactive and capable of producing only the mutant phe­notype. But if two mutant alleles are located in two different genes, one chromosome of trans heterozygote will have the wild type allele of the other gene.
Therefore, the trans heterozygote will have functional product of both the genes and the wild type phenotype will be produced by complementation. The complementation test has proven to be useful in delimiting genes.
But, in many cases, this test does not provide evidences to delimit gene.
a. Dominant or co-dominant mutation.
b. Genes in which mutations occur that show intragenic complementation.
c. Polar mutation, i.e., mutation that affects the expression of adjacent genes.
d. The gene in question does not produce a diffusible gene product, e.g., proteins.
Some other genes—such as operator and promotor genes which generally occur in the operon—do not code for a polypeptide or an enzyme. Hence they can act only in the cis position and they cannot show complementa­tion. Therefore, such genes are called ‘cis- acting gene.’
Fine Structure of Gene:
We have already discussed that there can be several sites in a gene, each capable of be­ing independently involved in mutational and re-combinational events. Therefore, a gene is neither a functional nor a re-combinational unit but is a complex locus whose fine structure should be studied.
The most extensive study on the fine structure of gene was undertaken by Seymour Benzer for a locus in T4 bacteriophage infecting E. coli. This locus is known as rπ locus.
T4 bacteriophage contains a linear molecule of DNA of about 200,000 base pair long which is packed within its head (Fig. 15.4). When T4 bacteriophage infects E. coli the bacterial cell lyses in about 20-25 minutes releasing 200-300 progeny phage particles.
When the inoculum of E. coli cells are plated in a petridish containing semi-solid nutrient medium, it will produce an uniform confluent growth or lawn on the surface of nutrient medium after certain period of incubation at the appropriate temperature [Fig. 15.5(a)], If the isolated T4 bacteriophage particles are placed at different sites on the surface of bacterial lawns, T4 bacteriophage infect the bacterial cell and all the E. coli cells in the immediate surrounding vicinity of phage will be destroyed.
This leads to the development of a clear area in the bacterial lawn. The clear areas are called plaques which indicate the areas of infection and lysis of bacterial cell due to infection by phage and is characteristic of phage.
The plaques are surrounded by a fuzzy or turbid margin called halos which are produced due to a phenomenon called lysis inhibition [Fig. 15.5(b)], It is a delay in lysis of T4 infected E. coli cells as a consequence of a subsequent infection by another T4 particle. The ability of T4 phage to cause lysis of bacterial cell is controlled by gene(s) present in a specific locus called ‘r’ locus (r = rapid lysis).
S. Benger isolated over thousands of inde­pendent mutant strains carrying mutation in the r locus (Fig. 15.6). Most of the r mutants map and classify into three distinct loci called r I r II and r III . The mutants can be recognised to some extent on the basis of the morphology of plaques, the ability of mutants to cause lysis of bacterial cell.
Mutants in the r II locus are easily recognised due to their inability to multiply in E. coli strain K12(λ) which has the chromosome of phage A integrated in its chromosome. How­ever, r II mutants grow rapidly in other strains of E. coli such as strain B and strain Ki2 lacking the λ chromosome.
The wild phage T4 r II+ makes small and fuzzy plaques both on B and K strains, whereas the r II mutants make large sharp plaques on E. coli strain B and K strains (Fig. 15.7). These distinguishable properties enabled Benzer to distinguish mutants and wild type phage with high efficiency. The r II mutants axe conditional lethals unable to grow in K12(λ) this property was exploited by Benzer for a fine genetic analysis of the r II locus.
Benzer isolated over 3,000 independent mu­tants of the r II locus and subjected them to complementation test. Phage carrying r II mu­tation can be easily identified by sterile tooth­pick transfers of phage from individual plaques growing on E. coli strain B (r II -permissive)
“Lawns” to lawn of E. coli strain K12 (λ) (r II restrictive) and lawns of E. coli strain B (Fig. 15.8). Each plaque to be tested (left side of Fig. 15.8) is stabled with a sterile toothpick which is subsequently touched to maxked axea in a petridish with a K12(λ) lawn (in the center of Fig. 15.8) and then to an identically marked area in a dish with an E. coli B lawn (right side of Fig. 15.8).
Mutants that fail to grow (are lethal) on K12(λ) (left side of the centre plate) can be recovered from the plaques on the E. coli B plates (right side of the Fig. 15.8).
If plaques develop on the E. coli B lawn, it indicates complementation between the two r II mutants used for co-infection, while an absence of plaques signifies a lack of complementation. Mutants at the r I and r III loci as well as r + phage (right side of the central plate) will grow on both K12(λ) and B. Benzer placed all r II mutants in two arbitrary groups named be A and B.
All the r” mutations were found to located in one of the two genes of cistron. Benzer designated these two genes r II A and r II B (Fig. 15.9).
The r II A region appears to consist of about 2,000 deoxyribonucleotide pairs. The A region transcribes a messenger RNA that translates an A polypeptide the B region is similarly responsible for a B polypeptide. B polypeptides are needed for lysis of K type E. coli cells. The wild type (r + ) phages produces both A and B polypeptides. A mutant produces normal B polypeptide but not A, and vice versa.
Hence infection only by identical r II A mutants or by identical r II B mutant alone can cause lysis of the host cells, because none of the phages can produce both A and B polypeptide (Fig. 15.10).
On the other hand, infection by two different mutants (one an r II A mutant and the other an r II B mutant) on the same host cell does result in lysis (Fig. 15.11). It indicates that regions A and B are functionally different and show complementation.
Benzer observed that with infection by two phages—one the wild type (r + ) and the other mutant in either A or B region, i.e., with mutation in the cis position—lysis occurred. But the lysis did not occur when the mutation A or B were in the trans configuration.
Thus, it was clear that mutation in one functional region (A or B) Eire complementary only to mutations in the other region and complementation is detectable by cis-trans test.
Each functional region is responsible for the production of a given polypeptide chain. Benzer defined the functional unit as cistron and conformed op­erationally more closely to what we commonly think as gene. This cistron, therefore, may be thought of as the gene at the functional level. There can be over a hundred points within a functional unit wherein a mutation can take place and cause a detectable phenotypic effect.
This means that a cistron is over hundred nucleotide pairs in length and there is some evidence that some cistrons may be as long as 30,000 nucleotide pairs. Actually each cistron represents a part of a gene which is responsible for coding of only one polypeptide chain of an enzyme that has two or more different polypep­tide chains in its complete enzymatic unit.
A cistron also includes initiating, terminating and any un-transcribed nucleotides.
(a) The Muton:
It is the smallest unit of DNA which, when altered, can give rise to a mutation. Study of the genetic code makes it clear that an alteration of a single nucleotide pair in DNA may result in a missense codon in transcribed mRNA (e.g., AGC—>AGA) or nonsense (e.g., UGC—> UGA). So a cistron may be expected to consist of many mutable units or mutons. The term muton was given by Benzer.
(b) The Recon:
It is the smallest part of DNA which is inter­changeable through crossing over and recombi­nation. Extremely delicate studies of recombi­nation in E. coli indicate that a recon consists of not more than two pairs of nucleotides, may be only one.
A recon may occur within a cistron. Thus a gene of classical concept is made up of a number of functional units—the cistrons— which consist of a number of recons and mutons (Fig. 15.12).
(i) Recombination Frequency:
The complementation test shows that all the r II mutants were located within A and B cistrons. In order to estimate the frequency of recom­bination between r II mutants, E. coli strains B cells are infected with a mixture of the two r II mutants.
If the crossing occurs between two chromosomes of mutant strain it yields one wild type and one double mutant type for each crossing over event (Fig. 15.13). Therefore, some of the progeny phage present in the lysate of the B strain (infected by a mixture of two r II mutant) would be of wild type.
The frequency of the wild type phage in the lysate is determined by plating lysate on the lawn of K12(λ) strain. Each wild type phage would produce a plaque on this lawn. This is a highly efficient selection system for wild type phage and as many as 10® progeny phage may be examined in a single petridish.
The number of plaques produce on Kj2(λ) represents the number of wild type phage particles in the lysate. A equal number of phage would have the double mutant produced due to recombination. Therefore, the number of recombination phage in the lysate would be twice the number of plaques produced on Ki2(λ).
Thus, the frequency of recombination may be measured as follows:
However, to map 3,000 mutations by only standard recombination test is a highly labo­rious task and is practically impossible because the number of all possible two-point crosses only (infection of E. coli cells by mixture of two mutants at a time) will be about 4 ½ illion, i.e., 3,000 x 2,999/2.
Hence Benzer was able to avoid such a laborious undertaking by developing a shortcut method of mapping that used overlapping deletion mutation. This technique is known as deletion mapping. It permits the deletion of recombination value of 0.0001 or even 0.00001%.
(ii) Deletion Mapping:
Benzer first mapped a number of r II mutants using the data of recombination test. He noted that some of these mutants did not show recom­bination with some other r II mutants. These mutants also failed to undergo reverse muta­tion, i.e., mutation to wild type r + .
Benzer classified these non-reverting, non-recombining r II mutations as deletion mutation. Benzer also proposed that these deletion mutations (multisite mutations) resulted from the deletion or loss of segments of DNA. These deletions were arranged in sets of overlapping deletions representing segments of different sizes in r II regions as shown in Fig. 15.14.
The principle involved in this method was that if a particular mutation presents in the region of a deletion represented by a r II mutant, then, on mixed infection with this deletion mutant, the point mutation will not be able to give rise to wild type, but if it falls outside the deletion regions it will be able to give rise to wild type and recombinant type.
The extents of the deleted segments can be analysed by crossing the deletion mutants to a set of reference point mutations which are previously mapped. Once a set of overlap­ping deletion has been mapped, their end- point will divide the region resolved by the longest deletion in a set of intervals A, B, C, D (Fig. 15.15).
When an unknown new mutant carrying a point mutation is isolated, the mutant can immediately be mapped to a defined interval by crossing the mutant with each of the overlapping deletion mutants. A mutant in interval D will not produce any wild type recombinant progeny in any of the four crosses. A mutation in interval C will recombine with deletion IV (Fig. 15.15) but not with the other three deletions, and so on.
In this manner, Benzer characterised with deleted segments of a large number of r II deletion mutants. This permitted him to divide the entire r II locus into 47 small segments (Fig. 15.16). A set of seven of these deletion mutants permitted him to divide the r II locus into 7 regions like A1 – A6 and B.
Each new r II mutant to be mapped was crossed pairwise with each of these seven deletion mutants and the presence of wild type (recombinants) phage particles counted in the progeny.
On the basis of this data a new r II mutant was localised in one of the- seven segments. (Table 15.1 and Fig. 15.17.) Once an unknown r II mutant is pointed in a segment, it is crossed to another set of deletion mutant’s which allows its locali­sation in a smaller sub-division of that segment.
The final mapping of r II mutants is done on the basis of recombination data from two and point crosses among mutants located within the concerned subsection of the r II locus. Benzer et al identified more than 300 sites of mutation that were separable by recombination. The progeny of mutation at different sites is highly variable.
Electron Microscope Heteroduplex Mapping:
The presence of genetically well-defined dele­tion mutations at the r II locus can also be de­termined using a technique called heteroduplex mapping. A DNA heteroduplex is a DNA molecule in which the two strands are not complementary.
One strand of a DNA double helix may contain one allele of the gene and the other strand may not be totally complementary and may carry of different alleles of the gene. The non complementary portions of DNA then form a heteroduplex which may vary in size from one mismatched base pair to large segments of the molecule.
Heteroduplex mapping involves in vitro preparation of DNA hetero-duplexes and their analysis by electron microscope. The heteroduplex may be prepared by mixing the denatured single-stranded DNA segments of wild type and mutant type followed by DNA renaturation.
The prepared hetero-duplexes between DNA from T4r + phage and DNA from each of several genetically well characterised r II deletion mutants. Thereafter they are analysed by electron microscope.
The results obtained estimates of 1,800±70 nucleotide pairs and 845 ± 50 nucleotide-pairs for the sizes of the r II A and r II B genes, respectively. These results combined with the extensive genetic data of Benzer et al provide a fairly clear picture of the fine structure of the r II locus.
(c) Overlapping Genes:
The presence of overlapping gene provides an interesting information for the study of fine structure of a gene. It is generally accepted that the boundaries of neighbouring genes do not overlap.
The study of nucleotide sequences of φ x 174 bacteriophage has clearly resolved that out of total 10 genes of φ x 174, two are located entirely within the coding sequences of two different genes. A third overlaps the sequences of three different genes. This surprising result has important genetic implication for the study of fine structure of gene.
(d) Fine Structure of Genes in Eukaryotes:
Complementation and recombination study have been used to prepare fine structure maps of several eukaryotic genes. By this technique, genetic fine structure maps have now been constructed for many genes of Drosophila maps have also been worked out for several other higher animals and higher plants.
One of the best examples of such a gene is the rosy (ry) eye locus of Drosophila which codes for the enzyme xanthine dehydrogenase. The different alleles of ry locus map at 10 different sites on the basis of recombination frequency (Fig. 15.18).
Many of the ry mutants do not show complementation (shown in upper line of the Fig. 18.18) while several others show complementary (shown in the lower line of the figure). The complementary allele may be located at the same site or at a site very close to one where non-complementary alleles are located.
The complementation of ry alleles is a case of intragenic complementation. The recovery of wild type recombination is very easy because rosy mutants are conditional lethals. As a result, wild type recombination produced from the heterozygotes for ry 2 ry 3 alleles can be easily isolated and counted by growing their progeny on a purine supplemented medium, on this medium only wild type progeny would survive.
Besides rosy locus, fine structure maps of gene of many other eukaryotes have been prepared like white (w) eye, notch (N) wing, lozenge (lz) eye, zetse (another eye colour locus near the white locus) etc. loci of Drosophila, waxy (wx) and other loci of maize, some loci of yeast.
Analysis and mapping of eukaryotic gene have also got some limitations due to:
i. Examining enough progeny of a cross to detect rare intragenic recombination in eukaryotes is a laborious job.
ii. In many cases, determining how many genes are present at a locus has proven difficult in eukaryotes. This problem arises due to the presence of complex loci.
iii. Complementation tests have often yielded ambiguous results—due to the occurrence of intragenic complementation. Delimiting genes of eukaryotes by complementation test should be done, whenever possible, using amorphic or null mutation (mutation resulting in no gene product) to minimize the possibility of confounding effects of intragenic complementation.
In eukary­otes, however, some genes have interesting structural features which are not found in most prokaryotes.
Therefore, our view of fine structure of any gene as discussed earlier may be partly ambiguous due to use of a specific recombination system. Further, the distances between genes on a genetic map may not correspond to the distances between them in the DNA molecule of which they are a part at the molecular level. There may also be present gaps or a genetic map due to non-availability of mutants in that region.
At the molecular level the fine structure of a gene can be resolved by modern genetic mapping through determination of nucleotide sequence of the concerned DNA segment. Alternatively we can prepare a genetic map by breaking the DNA at specific sites with the help of restriction endonucleases which are specific in recognising very short DNA sequences and cutting the DNA at these specific sites.
These sites of breakage can be identified and mapped in eukaryotes. This modern technique for in prokaryotes to give rise to a restriction genetic mapping at the molecular level has been map.
Scientific journal articles for further reading
Bratko D, Butković A, Vukasović T. Heritability of personality. Psychological Topics, 26 (2017), 1, 1-24.
Manuck SB, McCaffery JM. Gene-environment interaction. Annu Rev Psychol. 201465:41-70. doi: 10.1146/annurev-psych-010213-115100. PubMed: 24405358
Power RA, Pluess M. Heritability estimates of the big five personality traits based on common genetic variants. Translational Psychiatry (2015) 5, e604 doi:10.1038/tp.2015.96 published online 14 July 2015. PubMed: 26171985 PubMed Central: PMC5068715
Birds of a different color: Three major genes set feather hue in pigeons
Scientists at the University of Utah identified mutations in three key genes that determine feather color in domestic rock pigeons. The same genes control pigmentation of human skin.
"Mutations in these genes can be responsible for skin diseases and conditions such as melanoma and albinism," says Michael Shapiro, associate professor of biology and senior author of the study published online Feb. 6 in the journal Current Biology.
"In humans, mutations of these genes often are considered 'bad' because they can cause albinism or make cells more susceptible to UV (ultraviolet sunlight) damage and melanoma because the protective pigment is absent or low," says Eric Domyan, a biology postdoctoral fellow and first author of the study. "In pigeons, mutations of these same genes cause different feather colors, and to pigeon hobbyists that is a very good thing."
Pigeon breeders have drawn on their centuries-long experience to produce about 350 distinct pigeon breeds, focusing particularly on beak shape, plumage color and feather ornaments on the head, feet, beaks and elsewhere. But until this study, the specific mutations that control color in rock pigeons (Columba livia) were unknown.
"Across all pigeon breeds, mutations in three major genes explain a huge amount of color variation," Shapiro says.
Various forms of a gene named Tyrp1 make pigeons either blue-black (the grayish color of common city pigeons), red or brown. Mutations of a second gene, named Sox10, makes pigeons red no matter what the first gene does. And different forms of a third gene, named Slc45a2, make the pigeons' colors either intense or washed out.
The scientists discovered how pigeons' feather color is determined by different versions of these three genes -- known as variants or alleles -- and by what are called "epistatic" interactions, in which one gene obscures the effects of other genes.
"Our work provides new insights about how mutations in these genes affect their functions and how the genes work together," Shapiro says. "Many traits in animals, including susceptibility to diseases such as cancer, are controlled by more than one gene. To understand how these genes work together to produce a trait, we often have to move beyond studies of humans. It's difficult to study interactions among the genes in people."
"Both Tyrp1 and Sox10 are potential targets for treatment of melanoma," he adds. "Mutations in Slc45a2 in humans can lead to changes in skin color, including albinism (lack of skin color)."
Different versions of the three major pigeon-color genes affect the relative proportions of major forms of the melanin pigment &minus eumelanin and pheomelanin &minus and their distribution within cells. Eumelanin provides black and brown pigmentation, while pheomelanin provides red and yellow pigmentation of feathers. Interplay among the three major genes is complex, resulting in diverse coloration of pigeons.
"Mutations in one gene determine whether mutations in a second gene have an effect on an organism," Domyan says. In other words, one gene can mask the effects of another in relation to pigeon color.
The three pigment genes don't control how the colors are distributed in patterns on pigeons' bodies, such as white patches of feathers on some breeds. The genetics of color patterns remains to be determined.
Shapiro and Domyan conducted the study with several University of Utah co-authors: human genetics professor Mark Yandell, biology lab technician Michael Guernsey, genetics doctoral student Zev Kronenberg, former Huntsman Cancer Institute researchers Sancy Leachman and Pamela Cassidy, and biology undergraduate student Anna Vickrey. Other co-authors were Shreyas Krishnan, Clifford Rogers and John Fondon III from the University of Texas at Arlington and Raymond Boissy from the University of Cincinnati College of Medicine.
The study was funded by the National Science Foundation, Burroughs Wellcome Fund, National Institutes of Health, Huntsman Cancer Foundation and the Tom C. Mathews Jr. Familial Melanoma Research Clinic Endowment.
Breaking the Color Code
The scientists showed that feather colors in 82 breeds of pigeons could be explained by various combinations of the three genes and their different versions.
"Color is one of the most important traits to breeders &minus it makes a pretty pigeon," Shapiro says. Tinkering by breeders led to great color diversity in pigeons across the centuries, providing scientists with perfect specimens to study pigmentation genetics.
Shapiro and co-workers found that versions of the Tyrp1 gene were responsible for determining three basic pigeon colors: blue-black, ash-red, and brown. Blue-black color of pigeons is considered "normal," because neither Tyrp1 nor the other two major color genes contain mutations in these pigeons. City pigeons typically are this color.
Even before the rise of genetics, "Darwin realized that blue-black was the ancestral pigeon color, and that the various domestic rock pigeon breeds represented a single species," Shapiro says. When Darwin crossed pigeons of different colors, blue-black pigeons consistently appeared among the progeny.
Here's how the three genes work:
-- The Tyrp1 gene produces a protein that helps make the pigment eumelanin. Pigeons with blue-black feathers have normal Tyrp1. Ash-red and brown birds pigeons contain different mutations in the Tyrp1 gene, which leads to less or different pigmentation.
-- Mutations that affect the Sox10 gene override colors determined by various versions of the Tyrp1 gene. Regardless of whether the Tyrp1 version makes pigeons blue-black, ash-red or brown, mutations that regulate the Sox10 gene result in red pigeons.
-- Mutation of the Slc45a2 gene decreases the intensity of colors determined by Tyrp1, Sox10 and their mutants. Depending on the version of the Tyrp1 gene -- blue-black, ash-red, and brown &minus pigeons harboring the mutant Slc45a2 gene still display the same colors, but in watered-down or diluted versions, less intense than those with normal Slc45a2. For example, a pigeon with both the ash-red version of Tyrp1 and the mutant Slc45a2 gene has ash-yellow feathers. Pigeons with Sox10 and Slc45a2 mutations are yellow, which is the dilute form of red.
Most of the pigeon blood and feather samples used in the study were collected at pigeon shows in Utah, where breeders from across the country flocked to display their pigeons. After extracting and sequencing DNA from the samples, the researchers compared DNA sequences among the pigeons and observed that specific versions of genes associated with specific feather colors.
- Essay on the Introduction to the Process of Sex Determination
- Essay on the Chromosome Theory of Sex Determination
- Essay on Animals with Heterogametic Females
- Essay on the Process of Sex Determination in Human Beings
- Essay on Genic Balance Theory of Sex Determination in Drosophila
- Essay on Haplodiploidy and Sex Determination in Hymenoptera
- Essay on the Process of Sex Determination in Coenorhabditis Elegans
- Essay on Environmental Factors and Sex Determination
Essay # 1. Introduction to the Process of Sex Determination :
In nature a large number of diverse mechanisms exist for determination of sex in different species. The fruit fly Drosophila melanogaster and human beings are very important in the development of genetic concepts because in these two organisms, and in many others, individuals normally occur in one of two sex phenotypes, male or female.
In these species males produce male gametes, sperm, pollen or microspores while females produce female gametes namely, eggs, ovules or macrospores. In many species the two sexes are phenotypically indistinguishable except for the reproductive organs. Sex determination is aimed at identifying the factors responsible to make an organism a male or female or in some cases a hermaphrodite. So far the mechanism of sex determination has been related to the presence of sex chromosomes whose composition differs in male and female sexes.
However, in recent years sex determination has been differentiated from sex differentiation, and sex determination mechanism is explained more on the basis of the specific genes located on sex chromosomes and autosomes. Sex determination is recognized as a process in which signals are initiated for male or female developmental patterns.
During sex differentiation, events occur in definite pathways leading to the development of male and female phenotypes and secondary sexual characters. Significant progress has been made in understanding the mechanism of sex in human beings and other mammals and new genes have been identified.
Essay # 2. Chromosome Theory of Sex Determination :
Sex determination in higher animals is controlled by the action of one or more genes. The testis determining factor (TDF) gene is the dominant sex determining factor in human beings. Hemking a German biologist identified a particular nuclear structure throughout the spermatogenesis in some insects. He named it as “X-body” and showed that sperm differed by its presence or absence. The X body was later found to be a chromosome that determined sex. It was identified in several insects and is known as the sex or X chromosome.
Thus, the chromosome theory of sex determination states that female and male individuals differ in their chromosomes. Chromosomes can be differentiated into two types, autosomes and sex chromosomes. Sex chromosomes carry genes for sex. In some animals, females have one more chromosome than males, thus they have two X chromosomes and males have only one.
Females are therefore cytologically XX and males are XO, where ‘O’ denotes the absence of X chromosome. During meiosis in the female the 2X chromosome pairs and separates producing eggs that contain a single X chromosome. Thus all eggs are of the same type containing only one X chromosome.
During meiosis in the male, the single X chromosome moves independently of all the other chromosomes and is incorporated into half of the sperm, the other half do not have any X chromosome. Thus, two types of sperms are produced, one with X chromosome and the other without the X chromosome or designated as ‘O’.
When the sperm and eggs unite, two types of zygotes are produced XX that develop into females and XO that develop into males. Because both of these types are equal in number, the reproductive mechanism preserves a 1:1 ratio of males to females.
In many animals, including human beings, males and females have the same number of chromosomes. This numerical equality is due to the presence of a chromosome in the male called the ‘Y’ chromosome, which pairs with the X. During meiosis in the male, the X and Y-chromosomes separate from each other producing two types of sperm, one type with X chromosome and the other type having Y chromosome.
The frequencies of the two types are approximately equal. Females with XX chromosomes produce only one type of eggs, all with X chromosome. In random fertilization, approximately half of the zygotes are with XX chromosomes and the other half with XY chromosomes leading to a sex ratio of 1:1.This mechanism is called XX – XY type of sex determination.
The XY mechanism is more prevalent than the XO mechanism. The XY type is considered characteristic in higher animals and occurs in some plants. This mechanism is operative in Drosophila melanogaster and human beings. Both species exhibit the same pattern of transmission of X and Y chromosomes in normal individuals in – natural populations. In human beings, the X chromosome is considerably longer than the Y chromosome.
The total complement of human chromosomes includes 44 autosomes: XX in the female and XY in the male. Eggs produced by the female in oogenesis have a complement of 22 autosomes plus an X chromosome. Sperm from the male have the same autosomal number and either an X or a Y chromosome. Eggs fertilized with sperm containing a Y chromosome result in zygotes that develop into males those fertilized with sperm containing an X chromosome develop into females.
In animals with XX-XY mechanism of sex determination, females (XX) produce gametes that have the same chromosome composition (one X plus one set of autosomes). These females are homogametic sex as all the gametes are the same. The males of these animals are heterogametic as they produce two types of gametes, one half containing one X chromosome plus one set of autosomal chromosomes and the other one half contain one Y chromosome plus one set of autosomes.
Essay # 3. Animals with Heterogametic Females:
In many birds, moths and some fish, the sex determination mechanism is identical to the XX-XY mechanism but the females are heterogametic (ZW) and males are homogametic (ZZ). This mechanism of sex determination is called ZZ-ZW.
In this mechanism the relationship between sex chromosomes and sex phenotypes is reversed. In birds the chromosome composition of the egg determines the sex of the offspring, whereas in humans and fruit flies, the chromosome composition of the sperm determines the sex of the offspring.
Essay # 4. Process of Sex Determination in Human Beings:
In human beings, sex is determined by the number of X chromosomes or by the presence or absence of the Y chromosome. In human beings and other placental mammals, maleness is due to a dominant effect of the Y chromosome. The dominant effect of the Y chromosome is manifested early in development when it directs the primordial gonads to differentiate into testes.
Once the testes are formed, they secrete testosterone that stimulates the development of male secondary sexual characteristics. Testis determining factor (TDF) is the product of a gene called SRY (Sex determining Region of Y), which is located in the short arm of the Y chromosome of the mouse. SRY was discovered in unusual individuals whose sex was not consistent with their chromosome constitution – males with XX chromosomes and females with XY chromosomes.
Some of the XX males carried a small piece of the Y chromosome inserted into one of the X chromosomes. It is evident that this small piece carried genes for maleness. Some of the XY females carried an incomplete Y chromosome. The part of the Y chromosome that was missing corresponded to the piece that was present in the XX males.
Its absence in the XY females prevented them from developing testes. These observations show that a particular segment of the Y chromosome was required for the development of the male. Further studies showed that the SRY gene is located in this male determining segment. Like that of the human SRY gene is present in the Y chromosome of the mouse and it specifies male development (Fig. 5).
After the formation of the testes, testosterone secretion initiates the development of male sexual characteristics. The hormone testosterone binds to receptors of several types of cells. This binding leads to the formation of a hormone – receptor complex that transmits signals to the cell instructing how to differentiate.
The combined differentiation of many types of cells leads to the development of male characteristic like beard, heavy musculature and deep voice. Failure of the testosterone signaling system leads to nonappearance of the male characters and the individual develops into a female. One of the reasons for failure is an inability to make the testosterone receptor (Fig. 6).
Individuals with XY chromosomal composition having this biochemical deficiency first develop into males. In such males, although testis is formed and testosterone secreted, it has no effect because it cannot reach the target cell to transmit the developmental signal. Individuals lacking the testosterone receptor therefore can change sexes during embryological development and acquire female sexual characteristics.
However, such individuals do not develop ovaries and remain sterile. This syndrome known as testicular feminization is due to a mutation in an X-linked gene, tfm that codes for the testosterone receptor. The tfm mutation is transmitted from mothers to sons who are actually phenotypically female in a typical X- linked manner.
Master Regulatory Gene:
In human beings irregular sex chromosome constitutions occur occasionally. Any number of X chromosomes (XXX or XXXX), in the absence of a Y chromosome give rise to a female. For maleness, the presence of a Y chromosome is essential and even if several X chromosomes are present (XXXXY), the presence of a single Y chromosome leads to maleness.
The Y chromosome induces the development of the undifferentiated gonad medulla into testis, whereas an XX chromosomal set induces the undifferentiated gonadal cortex to develop into ovaries. The gene on the Y chromosome that induces the development of testes is called as Testis Determining Factor (TDF). It has been isolated, characterized and found to encode a protein that regulates the expression of other genes.
Thus, the TDF gene is the master regulator gene that triggers the expression of large number of genes that produce male sex phenotype. In the absence of TDF gene, the genes that produce femaleness predominate and express to produce a female phenotype. The TDF exerts a very dominant effect on development of the sex phenotype.
Essay # 5. Genic Balance Theory of Sex Determination in Drosophila:
In Drosophila investigations by C.B. Bridges have shown that X chromosomes contain female determining genes and male determining genes are located on the autosomes and many chromosome segments are involved. The genie balance theory of sex determination in Drosophila explains the mechanism involved in sex determination in this fly.
The Y chromosome in Drosophila does not play any role in sex determination. Sex in this animal is determined by the ratio of X chromosomes to autosomes. Normal diploid insects have a pair of sex chromosomes, either XX or XY, and three pairs of autosomes. These are denoted by AA, each A representing one set of haploid autosomes. Flies with abnormal number of autosomes can be produced by genetic manipulation as shown in Table 1.
Whenever the ratio of X chromosomes to autosomes is 1.0 or above, the sex of the fly is female, and whenever it is 0.5 or less, the fly is male. If the ratio is between 0.5 and 1.0, it is an intersex with both male and female characters. In all these phenotypes, Y chromosome has no role to play but it is required for the fertility of the male. In Drosophila sex determination mechanism, an X-linked gene called Sex lethal (Sxl) plays an important role (Fig. 7).
A number of X linked genes sets the level of Sxl activity in a zygote. If the ratio between X chromosomes and autosomes is 1.0 or above, the Sxl gene becomes activated and the zygote develops into a female. If the ratio is 0.5 or less, the Sxl gene is inactivated and the zygote develops into a male. A ratio between 0.5 and 1.0 leads to mixing of signals and the zygote develops into an intersex with a mixing of male and female characters.
The sex ratio of X chromosomes to autosomes and the phenotype of Drosophila determination pathway in Drosophila has three components:
(i) A system to ascertain the X : A ratio in the early embryo,
(ii) A system to convert this ratio into a developmental signal, and
(iii) A system to respond to this signal by producing either male or female structures.
The system to ascertain the X : A ratio involves interactions between maternally synthesized proteins that have been deposited in the eggs cytoplasm and embryologically synthesized proteins that are coded by several X-linked genes. These latter proteins are twice as abundant in XX embryos as in XY embryos and therefore provide a means for counting the number of X chromosomes present.
Because the genes that encode these proteins effect the numerator of the X : A ratio, they are called numerator elements. Other genes located on the autosomes affect the denominator of X : A ratio and are therefore called as denominator elements. These encode proteins that antagonize the products of numerator elements (Fig. 8).
The system for ascertainment of the X : A ratio in Drosophila is therefore based on antagonism between X-linked (numerator) and autosomal (denominator) gene products. Once the X : A ratio is ascertained, it is converted into a molecular signal that controls expression of the X-linked sex lethal gene (Sxl), the master regulator of the sex determination pathway.
Early in development, this signal activates transcription of the Sxl gene from PE’ the gene’s ‘early’ promoter, but only in XX embryos. The early transcripts from this promoter are processed and translated to produce functional sex-lethal proteins, denoted Sxl. After only a few cell divisions, transcription from the PE promoter is replaced by transcription from another promoter, PM.
The so called maintenance promoter of the Sxl gene. Interestingly, transcription from the PM promoter is also initiated in XY embryo. However, the transcripts from PM are correctly processed only if Sxl protein is present. Consequently, in XY embryos, where this protein is not synthesized, the Sxl transcripts are alternately spliced to include an exon with a stop codon, and when these alternately spliced transcripts are translated, they generate a short polypeptide without regulatory function.
Thus, alternate splicing of the Sxl transcripts in XY embryos does not lead to the production of functional Sxl protein and in the absence of this protein, these embryos develop as males. In XX embryos, where Sxl protein was initially made in response to X : A signal, Sxl transcripts from the PM promoter are spliced to produce more Sxl proteins.
In XX embryos, this protein is therefore, a positive regulator of its own synthesis forming a feedback mechanism that maintains the expression of the Sxl proteins in XX embryos and prevents its expression in XY embryos. The Sxl protein also regulates the splicing of transcription from another gene in the sex determination pathways, transformers (tra). These transcripts can be processed in two different ways.
In chromosomal males, where the Sxl protein is absent, the splicing apparatus always leaves a stop codon in the second exon of the tra RNA. Thus, when spliced tra RNA is translated, it generates a truncated polypeptide. In females, where the Sxl protein is present, this premature stop codon is removed by alternate splicing in at least some of the transcripts. Thus, when they are translated, some functional transformer protein tra is produced. The Sxl protein therefore allows the synthesis of functional tra protein in XX embryos but not in XY embryos (Fig. 9).
The tra protein also turns out to be a regulator of RNA processing. Along with tra 2, a protein encoded by the transformer 2 (tra 2) gene, it encodes the expression of double sex (dsx) an autosomal gene that can produce two different proteins -through alternate splicing of its RNA. In XX embryos, where the tra protein is present, dsx transcripts are processed to encode a DSX protein that represses the genes required for male development.
Therefore, such embryos develop into females. In XY embryos, where the TRA protein is absent, dsx transcripts are processes to encode a DSX protein that represses the gene required for female development. Consequently, such embryos develop into males. The dsx gene is therefore, the switch point at which a male or female developmental pathway is chosen. From this point, different sets of genes are specifically expressed in males and females to bring about sexual differentiation.
Essay # 6. Haplodiploidy and Sex Determination in Hymenoptera:
In the order hymenoptera including bees, wasps, ants and sand flies, males develop parthenogenetically from unfertilized eggs and have a haploid chromosomal number (in honey bee drone, there are 16 chromosomes). The queen honeybee and workers develop from fertilized eggs and carry the diploid number of 32 chromosomes. Because the normal males are haploid and normal females are diploid, this mechanism is known as haplodiploidy.
The hemizygous, hortiozygous and heterozygous status of certain chromosome segments controls sex determination. Female determination depends on heterozygosity for part of a chromosome. If different forms of this segment of chromosome involved are designated Xa, Xb and Xc, then individuals of chromosome make up XaXb, XaXc and XbXc are all females.
Hemizygous individuals Xa, Xb, or Xc cannot be heterozygous and are therefore male. Genetic manipulations to produce homozygous diploid males showed that sex determination depends on the genetic composition of this region and not on diploidy versus haploidy (XaXa, XbXb, or XcXc).
Mosaics and Gynandromorphs:
Abnormal chromosomal behaviour in insects produces sexual mosaics or gynandromorphs. In these forms some parts of the animal are male and others are female. When such abnormal chromosomal transmission involves autosomes lodging genes that control easily recognized phenotypes, individuals may also be produced that are mosaic for phenotypes unrelated to sex phenotype. Some gynandromorphs in Drosophyla are bilateral intersexes (Fig. 10) with male color pattern body shape and sex comb on one half of the body and female characteristics on the other half of the body. Both male and female gonads and genitalia are present.
The reason for bilateral gynandromorphism is irregularity in mitosis at the first cleavage of the zygote (Fig. 11). A chromosome lags behind in division and does not arrive at the pole in tine to be included in the newly formed daughter nucleus. When one of the X chromosomes of an XX female zygote lags behind in the spindle, one daughter nucleus receives only one X chromosome, while the other receives two X chromosomes resulting in a mosaic body pattern.
One nucleus in the two nuclei stage would be XO male. If the cleavage plane is so oriented that one daughter nucleus goes towards the right, that part will give rise to all cells that make up the right half of the adult body and the other half gives rise to the left half. If the loss of chromosome occurs at a later stage in cell division, smaller parts of the adult body would be male.
Position and size of the mosaic sector are determined by the place and time of the division abnormality.
Essay # 7. Process of Sex Determination in Coenorhabditis Elegans:
Coenorhabditis elegans is a nematode hermaphrodite species having two X chromosomes and five pairs of autosomes. Occasionally animals with a single X chromosome and five pairs of autosomes are produced by meiotic non disjunction. These animals are males capable of producing sperms but not eggs. Hermaphrodites are females in their vegetative parts (soma) but mixed in their genetic composition.
The somatic sex determination pathway in C.elgans involves atleast 10 different genes. The tra-1 and tra-2 gene products are required for normal hermaphrodite development and that the her-1 gene product is needed for normal male development. The fem gene products fem-1, fem-2, fem-3 are also needed for normal male development. The gene her-1, encodes a secreted protein that is likely to be a signaling molecule.
The next gene, tra-2i encodes a membrane bound protein, which may function as a receptor for the her-1 signalling protein. The products of the fem genes are cytoplasmic proteins that may transduce the her-1 signal and the last gene in the pathway, tra-1 encodes a zinc finger type transcription factor, which may regulate the gene involved in sexual differentiation (Fig. 12).
In Coenorhabditis elegans the sex determination pathway involves a series of negative regulators of gene expression. In XO animals the secreted her-1 gene product apparently interacts with the tra-2 gene product, causing it to become inactive. This interaction allows the three fem gene products to be activated and they collectively inactivate the tra-1 gene product that is a positive regulator of female differentiation. Because the animal cannot develop as a hermaphrodite without active tra-1 protein, it develops into a male.
In XX animals, the her-1 protein is not formed, therefore its putative receptor, the tra-2 protein remains active. Active tra-2 protein causes the fem gene products to be inactivated, which in turn allows the tra-1 protein to stimulate differentiation of the female. The animal therefore develops into a hermaphrodite.
Sexual development in Caenorhabditis fundamentally depends on the X : A ratio, just as it does in Drosophila. The X : A ratio is somehow converted into a. molecular signal that controls sexual differentiation. The signal from the X : A ratio is directed into the sex determination and dosage compensation pathways through a short pathway involving at least four genes. One of these genes, xol -I is required in males but not in hermaphrodites. Three other genes, Sdc-1, Sdc-2 and Sdc-3 are negatively regulated by Xol-i. These Sdc genes are needed in hermaphrodites but not in males.
Development of animals is sensitive to an imbalance in the number of genes. Normally each gene is present in two copies. Departures from this condition, either up or down can produce abnormal phenotypes and sometimes even death. It is therefore, puzzling that many species have a sex determination system based on females with two X chromosomes and males with only one X chromosome.
Normal females have IX chromosomes when male has IX chromosome. This is an unique situation as the number of chromosomes is same in males and females. Such disparities or differences create a “genetic dosage” problem between males and females for all the X-linked genes.
Some females have two copies of X-chromosome and males only one. Therefore, there is potential for females to produce twice as much of each gene product for all the X-linked genes. For compensating this dosage problem, it is proposed that one of the X-chromosome becomes heterochromatin in the case of the female, so that dosage of genetic information expressed in both females and males is equal.
Dosage Compensation in Drosophila:
In Drosophila dosage compensation of X-linked genes is achieved by an increase in the activity of these genes in males. This phenomenon, called “hyperactivation” involves complex of different proteins that binds to many sites on the X-chromosome in males and triggers a doubling of gene activity. When this protein complex does not bind, as in the case of females, hyperactivation of X-linked genes does not occur. In this way total X-linked gene activity in males and females is approximately equal (Fig. 13).
Dosage Compensation in Humans:
In human beings dosage compensation of X-linked genes is achieved by the “inactivation” of one of the females X-chromosomes. This mechanism was first proposed by Mary Lyon in 1961. The chromosome to be inactivated is chosen at random. Once chosen it remains inactivated in all the descendants of that cell. In human embryos sex chromatin bodies have been observed by the 16 th day of gestation. Some human traits are influenced by both X chromosomes during the first 16 days. Later only one X chromosome is functional.
Thus, the female is a mosaic with some parts having the alternate allele expressed. X chromosome inactivation occurs only when at least two X chromosomes are present. When a number of X chromosomes are present in the same nucleus, all but one are inactivated. The number of sex chromatin bodies present after inactivation is one less than the number of X chromosomes present in the original cell.
Dosage Compensation in Caenorhabditis Elegans:
In C.elegans dosage compensation involves the partial repression of X-linked genes in the somatic cells of hermaphrotites. In C.elegans dosage compensation is achieved by “hypoactivating” the two X chromosomes in XX hermaphrodites.
Essay # 8. Environmental Factors and Sex Determination:
The environmental factors determine whether an individual develops into a male and female. They live as parasites in the reproductive tract of the well developed and bigger female. In male all organs except the reproductive system are degenerate. During reproduction, the female releases eggs into the seawater. The eggs hatch out to release young worms. Some of the young worms reach the proboscis of the female and become males.
They reach the female reproductive tract and lie as permanent parasites on the female. The young worms, which fail to reach a female, develop to become females. Genetic determiners for both the sexes are present in all young worms. It has been observed that the young worms become attracted towards the extracts of the female proboscis and become males.
In some reptiles, temperature plays an important role in determining the sex. In the turtle Chrysema picta incubation of eggs prior to hatching at high temperature leads to the development of females. However, in the lizard
Agama high incubation temperature leads to male progeny.
Although the segregation of specific sex determining genes and chromosomes is responsible for sex in most animals, the genetic potential for both maleness and femaleness exists in every zygote and some specific factor in the environment triggers the expression of maleness or femaleness producing genes resulting in the production of male phenotype or female phenotype.
Scientific journal articles for further reading
Armour JA, Davison A, McManus IC. Genome-wide association study of handedness excludes simple genetic models. Heredity (Edinb). 2014 Mar112(3):221-5. doi:10.1038/hdy.2013.93. Epub 2013 Sep 25. PubMed: 24065183. Free full-text available from PubMed Central: PMC3931166.
Brandler WM, Morris AP, Evans DM, Scerri TS, Kemp JP, Timpson NJ, St Pourcain B, Smith GD, Ring SM, Stein J, Monaco AP, Talcott JB, Fisher SE, Webber C, Paracchini S. Common variants in left/right asymmetry genes and pathways are associated with relative hand skill. PLoS Genet. 20139(9):e1003751. doi: 10.1371/journal.pgen.1003751. Epub 2013 Sep 12. PubMed: 24068947. Free full-text available from PubMed Central: PMC3772043.
Brandler WM, Paracchini S. The genetic relationship between handedness and neurodevelopmental disorders. Trends Mol Med. 2014 Feb20(2):83-90. doi: 10.1016/j.molmed.2013.10.008. Epub 2013 Nov 23. Review. PubMed: 24275328. Free full-text available from PubMed Central: PMC3969300
de Kovel CGF, Francks C. The molecular genetics of hand preference revisited. Sci Rep. 2019 Apr 129(1):5986. doi: 10.1038/s41598-019-42515-0. PubMed: 30980028 Free full-text available from PubMed Central: PMC6461639.
McManus IC, Davison A, Armour JA. Multilocus genetic models of handedness closely resemble single-locus models in explaining family data and are compatible with genome-wide association studies. Ann N Y Acad Sci. 2013 Jun1288:48-58. doi:10.1111/nyas.12102. Epub 2013 Apr 30. PubMed: 23631511. Free full-text available from PubMed Central: PMC4298034.
Genotype and Phenotype
Evelyn Bailey - HD Image based on Original Image by Steve Berg
From Mendel's law of segregation, we see that the alleles for a trait separate when gametes are formed (through a type of cell division called meiosis). These allele pairs are then randomly united at fertilization. If a pair of alleles for a trait are the same, they are called homozygous. If they are different, they are heterozygous.
The F1 generation plants (Figure A) are all heterozygous for the pod color trait. Their genetic makeup or genotype is (Gg). Their phenotype (expressed physical trait) is green pod color.
The F2 generation pea plants show two different phenotypes (green or yellow) and three different genotypes (GG, Gg, or gg). The genotype determines which phenotype is expressed.
The F2 plants that have a genotype of either (GG) or (Gg) are green. The F2 plants that have a genotype of (gg) are yellow. The phenotypic ratio that Mendel observed was 3:1 (3/4 green plants to 1/4 yellow plants). The genotypic ratio, however, was 1:2:1. The genotypes for the F2 plants were 1/4 homozygous (GG), 2/4 heterozygous (Gg), and 1/4 homozygous (gg).