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29.3: Genetic Linkage - Biology

29.3: Genetic Linkage - Biology


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In the simple models we’ve seen so far, alleles are assumed to be passed on independently of each other. This is termed genetic linkage.

The , also known as Mendel’s second law states:

Alleles of different genes are passed on independently from parent to offspring.

When this “law” holds, there is no correlation between different polymorphisms and the probability of a haplotype (a given set of polymorphisms) is simply the product of the probabilities of each individual polymorphism.

In the case where the two genes lie on different chromosomes this assumption of independence generally holds, but if the two genes lie on the same chromosome, they are more often than not passed on together. Without genetic recombination events, in which segments of DNA on homologous chromosomes are swapped (crossing-over), the alleles of the two genes would remain perfectly correlated. With however, the correlation between the genes will be reduced over several generations. Over a suitably long time interval, recombination will completely remove the linkage between two polymorphisms; at which point they are said to be in equilibrium. When, on the other hand, the polymorphisms are correlated, we have Linkage Disequilibrium (LD). The amount of disequilibrium is the difference between the observed haplotype frequencies and those predicted in equilibrium.

The linkage disequilibrium can be used to measure the difference between observed and expected assortments. If there are two alleles (1 and 2) and two loci (A and B) we can calculate haplotype probabilities and find the expected allele frequencies.

• Haplotype frequencies

– P(A1)=x11

– P(B1)=x12

– P(A2)=x21

– P(B2)=x22

• Allele frequencies

– P11 = x11 + x12

– P21 = x21 + x22

– P12 = x11 + x21

– P22 = x12 + x22

• D=P11 *P22P12 *P21
Dmax, the maximum value of D with given allele frequencies, is related to D in the following equation:

[D^{prime}=frac{D}{D_{max }} onumber]

D' is the maximum linkage disequilibrium or complete skew for the given alleles and allele frequencies. Dmax can be found by taking the smaller of the expected haplotype frequencies P (A1, B2) or P (A2, B1). If the two loci are in complete equilibrium, then D' = 0. If D' = 1, there is full linkage.

The key point is that relatively recent mutations have not had time to be broken down by crossing-overs. Normally, such a mutation will not be very common. However, if it is under positive selection, the mutation will be much more prevalent in the population than expected. Therefore, by carefully combining a measure of LD and derived allele frequency, we can determine if a region is under positive selection.

Decay of is driven by recombination rate and time (in generations) and has an exponential decay. For a higher recombination rate, linkage disequilibrium will decay faster in a shorter amount of time. However, the background recombination rate is dicult to estimate and varies depending on the location in the genome. Comparison of genomic data across multiple species can help in determining these background rates.

29.3.1 Correlation Coefficient r2
Answers how predictive an allele at locus A is of an allele at locus B

[r^{2}=frac{D^{2}}{Pleft(A_{1} ight) Pleft(A_{2} ight) Pleft(B_{1} ight) Pleft(B_{2} ight)} onumber]

As the value of r2 approaches 1, the more two alleles at two loci are correlated. There may be linkage disequilibrium between two haplotypes, even if the haplotypes are not correlated at all. The correlation coecient is particularly interesting when studying associations of diseases with genes, where knowing the genotype at locus A may not predict a disease whereas locus B does. There is also the possibility where neither locus A nor locus B are predictive of the disease alone but loci A and B together are predictive.


Linkage of Genetics: Features, Examples, Types and Significance

When two or more characters of parents are transmitted to the offsprings of few generations such as F1, F2, F3 etc. without any recombination, they are called as the linked characters and the phenomenon is called as linkage.

This is a deviation from the Mendelian principle of independent assortment.

Mendel’s law of independent assortment is applicable to the genes that are situated in separate chromosomes. When genes for different characters are located in the same chromosome, they are tied to one another and are said to be linked.

They are inherited together by the offspring and will not be assorted independently. Thus, the tendency of two or more genes of the same chromosome to remain together in the process of inheritance is called linkage. Bateson and Punnet (1906), while working with sweet pea (Lathyrus odoratus) observed that flower colour and pollen shape tend to remain together and do not assort independently as per Mendel’s law of independent assortment.

When two different varieties of sweet pea—one having red flowers and round pollen grain and other having blue flower and long pollen grain were crossed, the F1 plants were blue flowered with long pollen (blue long characters were respectively dominant over red and round characters). When these blue long (heterozygous) hybrids were crossed with double recessive red and round (homozygous) individuals (test cross), they failed to produce expected 1:1:1:1 ratio in F2 generation. These actually produced following four combinations in the ratio of 7 : 1 : 1 : 7 (7 blue long : 1 blue round : 1 red long : 7 red round) (Fig. 5.6).

The above result of the test cross clearly indicates that the parental combinations (blue, long and red, round) are seven times more numerous than the non-parental combinations. Bateson and Punnet suggested that the genes (such as B and L) coming from the same parent (BBLL × bbll) tend to enter the same gamete and to be inherited together (coupling). Similarly, the genes (B and 1) coming from two different parents (such as BBLL x bbll), tend to enter different gametes and to be inherited separately and independently (repulsion).

Morgan’s View of Linkage:

Morgan (1910), while working on Drosophila stated that coupling and repulsion are two aspects of linkage. He defined linkage as the tendency of genes, present in the same chromosome, to remain in their original combination and to enter together in the same gamete.’

The genes located on the same chromosome and are being inherited together are known as linked genes, and the characters controlled by these are known as linked characters. Their recombination frequency is always less than 50%. All those genes which are located in the single chromosome form one linkage group. The total number of linkage group in an organism corresponds to the number of chromosome pairs. For example, there are 23 linkage groups in man, 7 in sweet pea and 4 in Drosophila melanogaster.

Features of Theory of Linkage:

Morgan and Castle formulated ‘The Chromosome Theory of Linkage’.

It has the following salient features:

1. Genes that show linkage are situated in the same chromosome.

2. Genes are arranged in a linear fashion in the chromosome i.e., linkage of genes is linear.

3. The distance between the linked genes is inversely proportional to the strength of linkage. The genes which are closely located show strong linkage, whereas those, which are widely separated, have more chance to get separated by crossing over (weak linkage).

4. Linked genes remain in their original combination during course of inheritance.

5. The linked genes show two types of arrangement on the chromosome. If the dominant alleles of two or more pairs of linked genes are present on one chromosome and their recessive alleles of all of them on the other homologue (AB/ab), this arrangement is known as cis-arrangement. However, if the dominant allele of one pair and recessive allele of second pair are present on one chromosome and recessive and dominant alleles on the other chromosome of a homologous pair (Ab/aB), this arrangement is called trans arrangement (Fig. 5.7).

Examples of Linkage:

Maize provides a good example of linkage. Hutchinson crossed a variety of maize having coloured and full seed (CCSS) with a variety having colourless and shrunken seeds (ccss). The gene C for colour is dominant over its colourless allele c and the gene S for full seed is dominant over its shrunken allele s. All the F1 plants produced coloured and full seed. But in a test cross, when such F1 females (heterozygous) are cross pollinated with the pollen from a plant having colourless and shrunken seeds (double recessive), four types of seeds are produced (Fig. 5.8).

From the above stated result it is clear that the parental combinations are more numerous (96.4%) than the new combination (3.6%). This clearly indicates that the parental characters are linked together. Their genes are located in the same chromosome and only in 3.6% individuals these genes are separated by crossing over. This is an example of incomplete linkage.

Morgan (1911) crossed an ordinary wild type Drosophila with grey body and long wings (BB VV) with another Drosophila (mutant type) with black body and vestigial wings (bbvv). All the hybrids in F1 generation are with grey bodies and long wings (BbVv) i.e., phenotypically like the wild type of parents. If now a male of F, generation (Bb Vv) is back crossed with a double recessive female (test cross) having black body and vestigial wings (bbvv) only parental combinations are formed in F2 generation without the appearance of any new combinations. The results indicate that grey body character is inherited together with long wings.

It implies that these genes are linked together. Similarly, black body character is associated with vestigial wing. Since only parental combinations of character appear in the offspring of F2 generation and no new or non-parental combinations appear, this shows complete linkage. Complete linkage is seen in Drosophila males.

Types of Linkage:

Depending upon the presence or absence of new combinations or non-parental combinations, linkage can be of two types:

If two or more characters are inherited together and consistently appear in two or more generations in their original or parental combinations, it is called complete linkage. These genes do not produce non-parental combinations.

Genes showing complete linkage are closely located in the same chromosome. Genes for grey body and long wings in male Drosophila show complete linkage.

(ii) Incomplete Linkage:

Incomplete linkage is exhibited by those genes which produce some percentage of non-parental combinations. Such genes are located distantly on the chromosome. It is due to accidental or occasional breakage of chromosomal segments during crossing over.

Significance of Linkage:

(i) Linkage plays an important role in determining the nature of scope of hybridization and selection programmes.

(ii) Linkage reduces the chance of recombination of genes and thus helps to hold parental characteristics together. It thus helps organism to maintain its parental, racial and other characters. For this reason plant and animal breeders find it difficult to combine various characters.


References

Burr B, Burr F A, Thompson K H, Albertson M C, Stuber C W (1988). Gene mapping with recombinant inbreds in maize. Genetics, 118: 519–526

Cregan P B, Jarvik T, Bush A L, Shoemaker R C, Lark K G, Kahler A L, Kaya N, van Toai T T, Lohnes D G, Chung J, Specht J E (1999). An integrated genetic linkage map of the soybean genome. Crop Science, 39: 1464–1490

Fang J G, Liu D J, Ma Z Q (2003). Constructing mango (Mangifera indica L.) genetic map using markers for double heterozygous loci. Molecular Plant Breeding, 1(3): 313–319 (in Chinese)

Fang X J, Wu W R, Tang J L (2001). “863” Biological High-technology Series—Crop DNA Marker Assisted Breeding. Beijing: Science Press (in Chinese)

Harushima Y, Yano M, Shomura A, Sato M, Shimano T, Kuboki Y, Yamamoto T, Lin S Y, Antonio B A, Parco A, Kajiya H, Huang N, Yamamoto K, Nagamura Y, Kurata N, Khush G S, Sasaki T (1998). A high-density rice genetic linkage map with 2275 markers using a single F2 population. Genetics, 148(1): 479–494

Hemmat M, Weeden N F, Manganris A G, Lawson D W (1994). Molecular marker linkage map for apple. J Heredity, 85: 4–11

JoinMap. Version 2.0 (1995). Netherlands: CPRO-DLO of Wageningen

Meyers B C, Chin D B, Shen K A, Sivaramakrishnan S, Lavelle D O, Zhang Z, Michelmore R W (1998). The major resistance gene cluster in lettuce is highly duplicated and spans several megabases. Plant Cell, 1998, 10: 1817–1832

Parniske M, Jones J D G (1999). Recombination between diverged clusters of the tomato Cf-9 plant disease resistance gene family. Plant Biology, 96(10): 5850–5855

Pierantoni L, Dondini L, Cho K-H, Shin I -S, Gennari F, Chiodini R, Tartarini S, Kang S -J, Sansavini S (2007). Pear scab resistance QTLs via a European pear (Pyrus communis) linkage map. Tree Genetics and Genomes, 3(4): 311–317

Qi X, Stain P, Lindhout P (1998). Use of locus-specific AFLP markers to construct a high-density molecular map in barley. Theor Appl Genet, 96(3–4): 376–384

Shen L Y (2005). Construction of genetic linkage map and mapping QTLs for some traits in Chinese jujube (Ziziphus jujuba Mill.). Dissertation for the Doctoral Degree. Baoding: Agricultural University of Hebei (in Chinese)

Smith J S C, Chin E C L, Shu H, Smith O S, Wall S J, Senior M L, Mitchell S E, Kresovich S, Ziegle J (1997). An evaluation of the utility of SSR loci as molecular markers in maize (Zea mays L.): Comparisons with data from RFLPs and pedigree. Theor Appl Genet, 95: 163–173

Tanksley S D, Ganal M W, Prince J P, de Vincente M C, Bonierbale M W, Brown P, Fulton T M, Giovanonni J J, Grandillo S, Martin G, Messeguer R, Miller J, Miller L, Paterson A, Pineda O, Roder M, Wing R, Wu W, Young N (1992). High density molecular linkage maps of the tomato and potato genomes: biological inferences and practical applications. Genetics, 132: 1141–1160

Tanksley S D, Ganal M W, Prince J P, de Vicente M C, Bonierbale M W, Broun P, Fulton T, Giovannoni J J, van der Vossen E A G, van der Voor J N A M, Rouppe t, Kanyuka K, Bendahmane A, Sandbrink H, Baulcombe D, Bakker J, Stiekema W J, Klein-Lankhorst R M (2000). Homologues of a single resistance-gene cluster in potato confer resistance to distinct pathogens: a virus and a nematode. The Plant Journal, 23(5): 567–576

Yamamoto T, Kimura T, Shoda M, Imai T, Saito T, Sawamura Y, Kotobuki K, Hayashi T, Matsuta N (2002). Genetic linkage maps constructed by using an interspecific cross between Japanese and European pears. Theor Appl Genet, 106(1): 9–18

Yu D N (1998). The molecular makers and genetic mapping in tomato. Acta Horiculturae Sinica, 25(4): 361–366 (in Chinese)


Biology 171

By the end of this section, you will be able to do the following:

  • Discuss Sutton’s Chromosomal Theory of Inheritance
  • Describe genetic linkage
  • Explain the process of homologous recombination, or crossing over
  • Describe chromosome creation
  • Calculate the distances between three genes on a chromosome using a three-point test cross

Long before scientists visualized chromosomes under a microscope, the father of modern genetics, Gregor Mendel, began studying heredity in 1843. With improved microscopic techniques during the late 1800s, cell biologists could stain and visualize subcellular structures with dyes and observe their actions during cell division and meiosis. With each mitotic division, chromosomes replicated, condensed from an amorphous (no constant shape) nuclear mass into distinct X-shaped bodies (pairs of identical sister chromatids), and migrated to separate cellular poles.

Chromosomal Theory of Inheritance

The speculation that chromosomes might be the key to understanding heredity led several scientists to examine Mendel’s publications and reevaluate his model in terms of chromosome behavior during mitosis and meiosis. In 1902, Theodor Boveri observed that proper sea urchin embryonic development does not occur unless chromosomes are present. That same year, Walter Sutton observed chromosome separation into daughter cells during meiosis ((Figure)). Together, these observations led to the Chromosomal Theory of Inheritance , which identified chromosomes as the genetic material responsible for Mendelian inheritance.


The Chromosomal Theory of Inheritance was consistent with Mendel’s laws, which the following observations supported:

  • During meiosis, homologous chromosome pairs migrate as discrete structures that are independent of other chromosome pairs.
  • Chromosome sorting from each homologous pair into pre-gametes appears to be random.
  • Each parent synthesizes gametes that contain only half their chromosomal complement.
  • Even though male and female gametes (sperm and egg) differ in size and morphology, they have the same number of chromosomes, suggesting equal genetic contributions from each parent.
  • The gametic chromosomes combine during fertilization to produce offspring with the same chromosome number as their parents.

Despite compelling correlations between chromosome behavior during meiosis and Mendel’s abstract laws, scientists proposed the Chromosomal Theory of Inheritance long before there was any direct evidence that chromosomes carried traits. Critics pointed out that individuals had far more independently segregating traits than they had chromosomes. It was only after several years of carrying out crosses with the fruit fly, Drosophila melanogaster, that Thomas Hunt Morgan provided experimental evidence to support the Chromosomal Theory of Inheritance.

Genetic Linkage and Distances

Mendel’s work suggested that traits are inherited independently of each other. Morgan identified a 1:1 correspondence between a segregating trait and the X chromosome, suggesting that random chromosome segregation was the physical basis of Mendel’s model. This also demonstrated that linked genes disrupt Mendel’s predicted outcomes. That each chromosome can carry many linked genes explains how individuals can have many more traits than they have chromosomes. However, researchers in Morgan’s laboratory suggested that alleles positioned on the same chromosome were not always inherited together. During meiosis, linked genes somehow became unlinked.

Homologous Recombination

In 1909, Frans Janssen observed chiasmata—the point at which chromatids are in contact with each other and may exchange segments—prior to the first meiosis division. He suggested that alleles become unlinked and chromosomes physically exchange segments. As chromosomes condensed and paired with their homologs, they appeared to interact at distinct points. Janssen suggested that these points corresponded to regions in which chromosome segments exchanged. We now know that the pairing and interaction between homologous chromosomes, or synapsis, does more than simply organize the homologs for migration to separate daughter cells. When synapsed, homologous chromosomes undergo reciprocal physical exchanges at their arms in homologous recombination , or more simply, “crossing over.”

To better understand the type of experimental results that researchers were obtaining at this time, consider a heterozygous individual that inherited dominant maternal alleles for two genes on the same chromosome (such as AB) and two recessive paternal alleles for those same genes (such as ab). If the genes are linked, one would expect this individual to produce gametes that are either AB or ab with a 1:1 ratio. If the genes are unlinked, the individual should produce AB, Ab, aB, and ab gametes with equal frequencies, according to the Mendelian concept of independent assortment. Because they correspond to new allele combinations, the genotypes Ab and aB are nonparental types that result from homologous recombination during meiosis. Parental types are progeny that exhibit the same allelic combination as their parents. Morgan and his colleagues, however, found that when they test crossed such heterozygous individuals to a homozygous recessive parent (AaBb × aabb), both parental and nonparental cases occurred. For example, 950 offspring might be recovered that were either AaBb or aabb, but 50 offspring would also result that were either Aabb or aaBb. These results suggested that linkage occurred most often, but a significant minority of offspring were the products of recombination.


In a test cross for two characteristics such as the one here, can the recombinant offspring’s predicted frequency be 60 percent? Why or why not?

Genetic Maps

Janssen did not have the technology to demonstrate crossing over so it remained an abstract idea that scientists did not widely believe. Scientists thought chiasmata were a variation on synapsis and could not understand how chromosomes could break and rejoin. Yet, the data were clear that linkage did not always occur. Ultimately, it took a young undergraduate student and an “all-nighter” to mathematically elucidate the linkage and recombination problem.

In 1913, Alfred Sturtevant, a student in Morgan’s laboratory, gathered results from researchers in the laboratory, and took them home one night to mull them over. By the next morning, he had created the first “chromosome map,” a linear representation of gene order and relative distance on a chromosome ((Figure)).


Which of the following statements is true?

  1. Recombination of the body color and red/cinnabar eye alleles will occur more frequently than recombination of the alleles for wing length and aristae length.
  2. Recombination of the body color and aristae length alleles will occur more frequently than recombination of red/brown eye alleles and the aristae length alleles.
  3. Recombination of the gray/black body color and long/short aristae alleles will not occur.
  4. Recombination of the red/brown eye and long/short aristae alleles will occur more frequently than recombination of the alleles for wing length and body color.

As (Figure) shows, by using recombination frequency to predict genetic distance, we can infer the relative gene order on chromosome 2. The values represent map distances in centimorgans (cM), which correspond to recombination frequencies (in percent). Therefore, the genes for body color and wing size were 65.5 − 48.5 = 17 cM apart, indicating that the maternal and paternal alleles for these genes recombine in 17 percent of offspring, on average.

To construct a chromosome map, Sturtevant assumed that genes were ordered serially on threadlike chromosomes. He also assumed that the incidence of recombination between two homologous chromosomes could occur with equal likelihood anywhere along the chromosome’s length. Operating under these assumptions, Sturtevant postulated that alleles that were far apart on a chromosome were more likely to dissociate during meiosis simply because there was a larger region over which recombination could occur. Conversely, alleles that were close to each other on the chromosome were likely to be inherited together. The average number of crossovers between two alleles—that is, their recombination frequency —correlated with their genetic distance from each other, relative to the locations of other genes on that chromosome. Considering the example cross between AaBb and aabb above, we could calculate the recombination’s frequency as 50/1000 = 0.05. That is, the likelihood of a crossover between genes A/a and B/b was 0.05, or 5 percent. Such a result would indicate that the genes were definitively linked, but that they were far enough apart for crossovers to occasionally occur. Sturtevant divided his genetic map into map units, or centimorgans (cM) , in which a 0,01 recombination frequency corresponds to 1 cM.

By representing alleles in a linear map, Sturtevant suggested that genes can range from linking perfectly (recombination frequency = 0) to unlinking perfectly (recombination frequency = 0.5) when genes are on different chromosomes or genes separate very far apart on the same chromosome. Perfectly unlinked genes correspond to the frequencies Mendel predicted to assort independently in a dihybrid cross. A 0.5 recombination frequency indicates that 50 percent of offspring are recombinants and the other 50 percent are parental types. That is, every type of allele combination is represented with equal frequency. This representation allowed Sturtevant to additively calculate distances between several genes on the same chromosome. However, as the genetic distances approached 0.50, his predictions became less accurate because it was not clear whether the genes were very far apart on the same or on different chromosomes.

In 1931, Barbara McClintock and Harriet Creighton demonstrated the crossover of homologous chromosomes in corn plants. Weeks later, Curt Stern demonstrated microscopically homologous recombination in Drosophila. Stern observed several X-linked phenotypes that were associated with a structurally unusual and dissimilar X chromosome pair in which one X was missing a small terminal segment, and the other X was fused to a piece of the Y chromosome. By crossing flies, observing their offspring, and then visualizing the offspring’s chromosomes, Stern demonstrated that every time the offspring allele combination deviated from either of the parental combinations, there was a corresponding exchange of an X chromosome segment. Using mutant flies with structurally distinct X chromosomes was the key to observing the products of recombination because DNA sequencing and other molecular tools were not yet available. We now know that homologous chromosomes regularly exchange segments in meiosis by reciprocally breaking and rejoining their DNA at precise locations.

Review Sturtevant’s process to create a genetic map on the basis of recombination frequencies here.

Mendel’s Mapped Traits

Homologous recombination is a common genetic process, yet Mendel never observed it. Had he investigated both linked and unlinked genes, it would have been much more difficult for him to create a unified model of his data on the basis of probabilistic calculations. Researchers who have since mapped the seven traits that Mendel investigated onto a pea plant genome’s seven chromosomes have confirmed that all the genes he examined are either on separate chromosomes or are sufficiently far apart as to be statistically unlinked. Some have suggested that Mendel was enormously lucky to select only unlinked genes whereas, others question whether Mendel discarded any data suggesting linkage. In any case, Mendel consistently observed independent assortment because he examined genes that were effectively unlinked.

Section Summary

Sutton and Boveri’s Chromosomal Theory of Inheritance states that chromosomes are the vehicles of genetic heredity. Neither Mendelian genetics nor gene linkage is perfectly accurate. Instead, chromosome behavior involves segregation, independent assortment, and occasionally, linkage. Sturtevant devised a method to assess recombination frequency and infer linked genes’ relative positions and distances on a chromosome on the basis of the average number of crossovers in the intervening region between the genes. Sturtevant correctly presumed that genes are arranged in serial order on chromosomes and that recombination between homologs can occur anywhere on a chromosome with equal likelihood. Whereas linkage causes alleles on the same chromosome to be inherited together, homologous recombination biases alleles toward an independent inheritance pattern.

Art Connections

(Figure) In a test cross for two characteristics such as the one shown here, can the predicted frequency of recombinant offspring be 60 percent? Why or why not?

(Figure) No. The predicted frequency of recombinant offspring ranges from 0% (for linked traits) to 50% (for unlinked traits).

(Figure) Which of the following statements is true?

  1. Recombination of the body color and red/cinnabar eye alleles will occur more frequently than recombination of the alleles for wing length and aristae length.
  2. Recombination of the body color and aristae length alleles will occur more frequently than recombination of red/brown eye alleles and the aristae length alleles.
  3. Recombination of the gray/black body color and long/short aristae alleles will not occur.
  4. Recombination of the red/brown eye and long/short aristae alleles will occur more frequently than recombination of the alleles for wing length and body color.

Free Response

Explain how the Chromosomal Theory of Inheritance helped to advance our understanding of genetics.

The Chromosomal Theory of Inheritance proposed that genes reside on chromosomes. The understanding that chromosomes are linear arrays of genes explained linkage, and crossing over explained recombination.

Glossary


Family studies and gene𠄾nvironment interaction

Epidemiologic studies of unipolar major depression have revealed a population prevalence of 2%�% and an age-adjusted risk for first-degree relatives of patients with unipolar major depression of 5%�%. 1 , 2 In a meta-analysis of 5 large and rigorously selected family studies of major depression, familiality in this disease was demonstrated by a relative risk of 2.8 for affected subject versus first-degree relative status. 3 Early age of onset and multiple episodes of depression seem to increase the familial aggregation, and different affective disorders are often present in the same family. 4 Relatives of patients with bipolar disorder also have an increased risk of unipolar depression, and affective disorders tend to coexist with anxiety in many families. 5 , 6 , 7

Twin and family-based studies have accrued considerable evidence that a complex genetic mechanism is involved in vulnerability to depressive disorders. 8 , 9 Compared with the general population, first-degree relatives of depressed individuals have a nearly 3-fold increase in their risk of developing a major depressive disorder. In general, twin studies of depressive adults suggest that genes and specific environmental factors are critical and that shared environmental factors, although important in less severe subtypes of depression, are possibly of less significance. 10 , 11 , 12 , 13 The heritability of unipolar depression appears to be remarkable, with estimates between 40% and 70%. Depression- associated genetic factors are largely shared with generalized anxiety disorder, whereas environmental determinants seem to be distinct. 14 , 15 , 16 This notion is consistent with recent models of emotional disorders, which view depression and anxiety as sharing common vulnerabilities but differing in dimensions including, for instance, focus of attention or psychosocial liability. Although life events may precipitate depression, examination of familial liability along with social adversity reveals that environmental effects tend to be contaminated by genetic influences. 16 , 17 The predisposition to suffer life events is likely to be influenced by shared family environment, and some events may be associated with genetic factors.

Whereas genetic research has typically focused either on depression-related traits or on major depressive disorders, with few investigations evaluating the genetic and environmental relation between the two, it is crucial to identify whether a certain quantitative trait pathogenetically influences the disorder or whether the trait is a syndromal dimension of the disorder. The concept of traits influencing disease liability also supports the hypothesis that a genetic predisposition, coupled with early life stress in critical stages of development, may result in a phenotype that is neurobiologically vulnerable to stress and may lower an individual's threshold for developing depression on additional exposure to stress.


63 Chromosomal Theory and Genetic Linkage

By the end of this section, you will be able to do the following:

  • Discuss Sutton’s Chromosomal Theory of Inheritance
  • Describe genetic linkage
  • Explain the process of homologous recombination, or crossing over
  • Describe chromosome creation
  • Calculate the distances between three genes on a chromosome using a three-point test cross

Long before scientists visualized chromosomes under a microscope, the father of modern genetics, Gregor Mendel, began studying heredity in 1843. With improved microscopic techniques during the late 1800s, cell biologists could stain and visualize subcellular structures with dyes and observe their actions during cell division and meiosis. With each mitotic division, chromosomes replicated, condensed from an amorphous (no constant shape) nuclear mass into distinct X-shaped bodies (pairs of identical sister chromatids), and migrated to separate cellular poles.

Chromosomal Theory of Inheritance

The speculation that chromosomes might be the key to understanding heredity led several scientists to examine Mendel’s publications and reevaluate his model in terms of chromosome behavior during mitosis and meiosis. In 1902, Theodor Boveri observed that proper sea urchin embryonic development does not occur unless chromosomes are present. That same year, Walter Sutton observed chromosome separation into daughter cells during meiosis ((Figure)). Together, these observations led to the Chromosomal Theory of Inheritance , which identified chromosomes as the genetic material responsible for Mendelian inheritance.


The Chromosomal Theory of Inheritance was consistent with Mendel’s laws, which the following observations supported:

  • During meiosis, homologous chromosome pairs migrate as discrete structures that are independent of other chromosome pairs.
  • Chromosome sorting from each homologous pair into pre-gametes appears to be random.
  • Each parent synthesizes gametes that contain only half their chromosomal complement.
  • Even though male and female gametes (sperm and egg) differ in size and morphology, they have the same number of chromosomes, suggesting equal genetic contributions from each parent.
  • The gametic chromosomes combine during fertilization to produce offspring with the same chromosome number as their parents.

Despite compelling correlations between chromosome behavior during meiosis and Mendel’s abstract laws, scientists proposed the Chromosomal Theory of Inheritance long before there was any direct evidence that chromosomes carried traits. Critics pointed out that individuals had far more independently segregating traits than they had chromosomes. It was only after several years of carrying out crosses with the fruit fly, Drosophila melanogaster, that Thomas Hunt Morgan provided experimental evidence to support the Chromosomal Theory of Inheritance.

Genetic Linkage and Distances

Mendel’s work suggested that traits are inherited independently of each other. Morgan identified a 1:1 correspondence between a segregating trait and the X chromosome, suggesting that random chromosome segregation was the physical basis of Mendel’s model. This also demonstrated that linked genes disrupt Mendel’s predicted outcomes. That each chromosome can carry many linked genes explains how individuals can have many more traits than they have chromosomes. However, researchers in Morgan’s laboratory suggested that alleles positioned on the same chromosome were not always inherited together. During meiosis, linked genes somehow became unlinked.

Homologous Recombination

In 1909, Frans Janssen observed chiasmata—the point at which chromatids are in contact with each other and may exchange segments—prior to the first meiosis division. He suggested that alleles become unlinked and chromosomes physically exchange segments. As chromosomes condensed and paired with their homologs, they appeared to interact at distinct points. Janssen suggested that these points corresponded to regions in which chromosome segments exchanged. We now know that the pairing and interaction between homologous chromosomes, or synapsis, does more than simply organize the homologs for migration to separate daughter cells. When synapsed, homologous chromosomes undergo reciprocal physical exchanges at their arms in homologous recombination , or more simply, “crossing over.”

To better understand the type of experimental results that researchers were obtaining at this time, consider a heterozygous individual that inherited dominant maternal alleles for two genes on the same chromosome (such as AB) and two recessive paternal alleles for those same genes (such as ab). If the genes are linked, one would expect this individual to produce gametes that are either AB or ab with a 1:1 ratio. If the genes are unlinked, the individual should produce AB, Ab, aB, and ab gametes with equal frequencies, according to the Mendelian concept of independent assortment. Because they correspond to new allele combinations, the genotypes Ab and aB are nonparental types that result from homologous recombination during meiosis. Parental types are progeny that exhibit the same allelic combination as their parents. Morgan and his colleagues, however, found that when they test crossed such heterozygous individuals to a homozygous recessive parent (AaBb × aabb), both parental and nonparental cases occurred. For example, 950 offspring might be recovered that were either AaBb or aabb, but 50 offspring would also result that were either Aabb or aaBb. These results suggested that linkage occurred most often, but a significant minority of offspring were the products of recombination.


In a test cross for two characteristics such as the one here, can the recombinant offspring’s predicted frequency be 60 percent? Why or why not?

Genetic Maps

Janssen did not have the technology to demonstrate crossing over so it remained an abstract idea that scientists did not widely believe. Scientists thought chiasmata were a variation on synapsis and could not understand how chromosomes could break and rejoin. Yet, the data were clear that linkage did not always occur. Ultimately, it took a young undergraduate student and an “all-nighter” to mathematically elucidate the linkage and recombination problem.

In 1913, Alfred Sturtevant, a student in Morgan’s laboratory, gathered results from researchers in the laboratory, and took them home one night to mull them over. By the next morning, he had created the first “chromosome map,” a linear representation of gene order and relative distance on a chromosome ((Figure)).


Which of the following statements is true?

  1. Recombination of the body color and red/cinnabar eye alleles will occur more frequently than recombination of the alleles for wing length and aristae length.
  2. Recombination of the body color and aristae length alleles will occur more frequently than recombination of red/brown eye alleles and the aristae length alleles.
  3. Recombination of the gray/black body color and long/short aristae alleles will not occur.
  4. Recombination of the red/brown eye and long/short aristae alleles will occur more frequently than recombination of the alleles for wing length and body color.

As (Figure) shows, by using recombination frequency to predict genetic distance, we can infer the relative gene order on chromosome 2. The values represent map distances in centimorgans (cM), which correspond to recombination frequencies (in percent). Therefore, the genes for body color and wing size were 65.5 − 48.5 = 17 cM apart, indicating that the maternal and paternal alleles for these genes recombine in 17 percent of offspring, on average.

To construct a chromosome map, Sturtevant assumed that genes were ordered serially on threadlike chromosomes. He also assumed that the incidence of recombination between two homologous chromosomes could occur with equal likelihood anywhere along the chromosome’s length. Operating under these assumptions, Sturtevant postulated that alleles that were far apart on a chromosome were more likely to dissociate during meiosis simply because there was a larger region over which recombination could occur. Conversely, alleles that were close to each other on the chromosome were likely to be inherited together. The average number of crossovers between two alleles—that is, their recombination frequency —correlated with their genetic distance from each other, relative to the locations of other genes on that chromosome. Considering the example cross between AaBb and aabb above, we could calculate the recombination’s frequency as 50/1000 = 0.05. That is, the likelihood of a crossover between genes A/a and B/b was 0.05, or 5 percent. Such a result would indicate that the genes were definitively linked, but that they were far enough apart for crossovers to occasionally occur. Sturtevant divided his genetic map into map units, or centimorgans (cM) , in which a 0,01 recombination frequency corresponds to 1 cM.

By representing alleles in a linear map, Sturtevant suggested that genes can range from linking perfectly (recombination frequency = 0) to unlinking perfectly (recombination frequency = 0.5) when genes are on different chromosomes or genes separate very far apart on the same chromosome. Perfectly unlinked genes correspond to the frequencies Mendel predicted to assort independently in a dihybrid cross. A 0.5 recombination frequency indicates that 50 percent of offspring are recombinants and the other 50 percent are parental types. That is, every type of allele combination is represented with equal frequency. This representation allowed Sturtevant to additively calculate distances between several genes on the same chromosome. However, as the genetic distances approached 0.50, his predictions became less accurate because it was not clear whether the genes were very far apart on the same or on different chromosomes.

In 1931, Barbara McClintock and Harriet Creighton demonstrated the crossover of homologous chromosomes in corn plants. Weeks later, Curt Stern demonstrated microscopically homologous recombination in Drosophila. Stern observed several X-linked phenotypes that were associated with a structurally unusual and dissimilar X chromosome pair in which one X was missing a small terminal segment, and the other X was fused to a piece of the Y chromosome. By crossing flies, observing their offspring, and then visualizing the offspring’s chromosomes, Stern demonstrated that every time the offspring allele combination deviated from either of the parental combinations, there was a corresponding exchange of an X chromosome segment. Using mutant flies with structurally distinct X chromosomes was the key to observing the products of recombination because DNA sequencing and other molecular tools were not yet available. We now know that homologous chromosomes regularly exchange segments in meiosis by reciprocally breaking and rejoining their DNA at precise locations.

Review Sturtevant’s process to create a genetic map on the basis of recombination frequencies here.

Mendel’s Mapped Traits

Homologous recombination is a common genetic process, yet Mendel never observed it. Had he investigated both linked and unlinked genes, it would have been much more difficult for him to create a unified model of his data on the basis of probabilistic calculations. Researchers who have since mapped the seven traits that Mendel investigated onto a pea plant genome’s seven chromosomes have confirmed that all the genes he examined are either on separate chromosomes or are sufficiently far apart as to be statistically unlinked. Some have suggested that Mendel was enormously lucky to select only unlinked genes whereas, others question whether Mendel discarded any data suggesting linkage. In any case, Mendel consistently observed independent assortment because he examined genes that were effectively unlinked.

Section Summary

Sutton and Boveri’s Chromosomal Theory of Inheritance states that chromosomes are the vehicles of genetic heredity. Neither Mendelian genetics nor gene linkage is perfectly accurate. Instead, chromosome behavior involves segregation, independent assortment, and occasionally, linkage. Sturtevant devised a method to assess recombination frequency and infer linked genes’ relative positions and distances on a chromosome on the basis of the average number of crossovers in the intervening region between the genes. Sturtevant correctly presumed that genes are arranged in serial order on chromosomes and that recombination between homologs can occur anywhere on a chromosome with equal likelihood. Whereas linkage causes alleles on the same chromosome to be inherited together, homologous recombination biases alleles toward an independent inheritance pattern.

Visual Connection Questions

(Figure) In a test cross for two characteristics such as the one shown here, can the predicted frequency of recombinant offspring be 60 percent? Why or why not?

(Figure) No. The predicted frequency of recombinant offspring ranges from 0% (for linked traits) to 50% (for unlinked traits).

(Figure) Which of the following statements is true?

  1. Recombination of the body color and red/cinnabar eye alleles will occur more frequently than recombination of the alleles for wing length and aristae length.
  2. Recombination of the body color and aristae length alleles will occur more frequently than recombination of red/brown eye alleles and the aristae length alleles.
  3. Recombination of the gray/black body color and long/short aristae alleles will not occur.
  4. Recombination of the red/brown eye and long/short aristae alleles will occur more frequently than recombination of the alleles for wing length and body color.

Review Questions

X-linked recessive traits in humans (or in Drosophila) are observed ________.

  1. in more males than females
  2. in more females than males
  3. in males and females equally
  4. in different distributions depending on the trait

The first suggestion that chromosomes may physically exchange segments came from the microscopic identification of ________.

Which recombination frequency corresponds to independent assortment and the absence of linkage?

Which recombination frequency corresponds to perfect linkage and violates the law of independent assortment?

Critical Thinking Questions

Explain how the Chromosomal Theory of Inheritance helped to advance our understanding of genetics.

The Chromosomal Theory of Inheritance proposed that genes reside on chromosomes. The understanding that chromosomes are linear arrays of genes explained linkage, and crossing over explained recombination.

Glossary


Genetic Linkage

the joint transfer of two or more genes from parents to offspring. Genetic linkage occurs because such genes reside on the same chromosome, that is, they belong to the same linkage group and therefore cannot be accidentally recom-bined in meiosis, which occurs in the inheritance of genes residing on different chromosomes.

Genetic linkage was discovered in 1906 by the English geneticists W. Bateson and R. Punnett, who discovered in experiments on the crossing of plants the tendency of some genes to transfer together, thus violating the law of the independent combination of traits. This tendency was correctly explained by T. H. Morgan and his associates, who discovered a similar phenomenon in their study of inherited traits in the fruit fly (Drosophila).

Genetic linkage is measured by the frequency at which crossover gametes or spores are formed by a heterozygote on jointly transferring genes. In these gametes or spores, the genes occur in new combinations rather than in the original combinations, owing to the crossing-over of those parts of the homologous chromosomes bearing the genes. In some bacteria, another measure of genetic linkage is the frequency of joint transmission by inheritance of various genes in conjugation, genetic transformation, and transduction. The extent of genetic linkage may vary among the sexes: it is generally greater in the heterogametic sex. Genetic linkage may even be complete, without crossing-over, in one of the sexes, for example, in male Drosophila or in female Asiatic silkworms (Bombyx morí). The extent of genetic linkage may also vary with the age of the parents and with temperature. In addition, it may vary in the presence of chromosomal rearrangement or of mutant genes that influence the extent of genetic linkage.


Epigenetic linkage of aging, cancer and nutrition

Epigenetic mechanisms play a pivotal role in the expression of genes and can be influenced by both the quality and quantity of diet. Dietary compounds such as sulforaphane (SFN) found in cruciferous vegetables and epigallocatechin-3-gallate (EGCG) in green tea exhibit the ability to affect various epigenetic mechanisms such as DNA methyltransferase (DNMT) inhibition, histone modifications via histone deacetylase (HDAC), histone acetyltransferase (HAT) inhibition, or noncoding RNA expression. Regulation of these epigenetic mechanisms has been shown to have notable influences on the formation and progression of various neoplasms. We have shown that an epigenetic diet can influence both cellular longevity and carcinogenesis through the modulation of certain key genes that encode telomerase and p16. Caloric restriction (CR) can also play a crucial role in aging and cancer. Reductions in caloric intake have been shown to increase both the life- and health-span in a variety of animal models. Moreover, restriction of glucose has been demonstrated to decrease the incidence of age-related diseases such as cancer and diabetes. A diet rich in compounds such as genistein, SFN and EGCG can positively modulate the epigenome and lead to many health benefits. Also, reducing the quantity of calories and glucose in the diet can confer an increased health-span, including reduced cancer incidence.


Chromosomal Theory of Inheritance

The speculation that chromosomes might be the key to understanding heredity led several scientists to examine Mendel’s publications and reevaluate his model in terms of chromosome behavior during mitosis and meiosis. In 1902, Theodor Boveri observed that proper sea urchin embryonic development does not occur unless chromosomes are present. That same year, Walter Sutton observed chromosome separation into daughter cells during meiosis ((Figure)). Together, these observations led to the Chromosomal Theory of Inheritance , which identified chromosomes as the genetic material responsible for Mendelian inheritance.


The Chromosomal Theory of Inheritance was consistent with Mendel’s laws, which the following observations supported:

  • During meiosis, homologous chromosome pairs migrate as discrete structures that are independent of other chromosome pairs.
  • Chromosome sorting from each homologous pair into pre-gametes appears to be random.
  • Each parent synthesizes gametes that contain only half their chromosomal complement.
  • Even though male and female gametes (sperm and egg) differ in size and morphology, they have the same number of chromosomes, suggesting equal genetic contributions from each parent.
  • The gametic chromosomes combine during fertilization to produce offspring with the same chromosome number as their parents.

Despite compelling correlations between chromosome behavior during meiosis and Mendel’s abstract laws, scientists proposed the Chromosomal Theory of Inheritance long before there was any direct evidence that chromosomes carried traits. Critics pointed out that individuals had far more independently segregating traits than they had chromosomes. It was only after several years of carrying out crosses with the fruit fly, Drosophila melanogaster, that Thomas Hunt Morgan provided experimental evidence to support the Chromosomal Theory of Inheritance.


Background

The Major Histocompatibility Complex (MHC) is a family of genes that play a major role in activating adaptive immune responses [1]. Some of these gene families code for transmembrane proteins that protect individuals from viral, bacterial and parasitic infections by presenting pathogen-derived peptides to T lymphocytes, which subsequently triggers an immune response. The MHC molecular region, called HLA in humans and Patr in chimpanzees, is very similar in these two species as orthologous genes involved in peptide presentation are physically arranged in a comparable way [2,3,4,5,6,7] (Fig. 1). These genes are organized into two classes that differ from each other based on major structural and functional differences between their corresponding proteins. The molecules expressed (on almost all nucleated cells) by the classical class I genes (named A, B and C) consist of one α chain, non-covalently bound to a small β2-microglobulin chain which is not encoded in the MHC region. The α1 and α2 domains of this heavy chain form the peptide-binding region (PBR) which presents short peptides (mostly nonamers) of intracellular origin at the cell surface to CD8+ cytotoxic T lymphocytes. In all classical MHC class I genes, the 2nd and 3rd exons encoding these two domains are highly polymorphic. Chimpanzees may also possess an additional class I A-like locus named Patr-AL which is in strong linkage disequilibrium with Patr-A [8, 9]. However this gene is not fixed but only present on a portion of the haplotypes. The MHC molecules encoded by the class II genes (named DP, DQ and DR) display a more specific tissue distribution limited to professional antigen presenting cells implicated in the immune response, i.e. mostly B lymphocytes, dendritic cells and macrophages. Contrary to class I, class II proteins are heterodimers composed of one α chain coded by a “A” gene (named DPA, DQA or DRA) and one β chain coded by a “B” gene (named DPB, DQB or DRB, respectively). The α1 and β1 domains of the α and β chains form the PBR, which in this case presents peptides (of about 12–15 amino acids) from mostly extracellular origin at the cell surface to CD4+ T-helper lymphocytes. The 2nd exon of most MHC class II “B” genes (which encodes the β1 domain) is highly variable, whereas that of “A” genes (which encodes the α1 domain) is much less polymorphic, except at the DQ loci. Most class II genes also exhibit one or more functional and/or non-functional (i.e. pseudogenic) copies (e.g. DRB1, DRB2, DRB3, etc. ) resulting from past duplications [5, 10,11,12,13,14,15,16], but only the four most polymorphic ones DPB1, DQB1, DQA1 and DRB1 are extensively studied.

Map of the human and chimpanzee MHC region showing average physical distances between the 7 loci under study in both species. The distances between loci (in Kb = kilobases) slightly vary between the two species but they have the same order of magnitude.

80 Kb stands for “physical distance between DQB1 and DRB1 is about 80 Kb”

The HLA region is amongst the most variable of the whole genome, with almost 26,000 HLA (class I and class II) alleles identified so far (November 2019, [17]). Its huge level of diversity and/or allelic variation observed within human populations is believed to be maintained by different kinds of balancing selection, most often in the form of heterozygote advantage towards a large variety of pathogens following a divergent allele advantage (DAA) model, although negative frequency-dependent (also named rare-allele advantage) and fluctuating selection in time and space also explain its remarkable variation [18,19,20,21,22]. These mechanisms maintain even HLA allele frequencies in most populations, with recurrent – although not systematic – deviations from neutral expectations towards a significant excess of heterozygotes [21, 23]. However, specific HLA alleles may also act as protective factors to highly prevalent diseases and be selected positively, one of the best examples being the putative increase of B*53 (B*53:01:01) and B*78 (B*78:01) frequencies in sub-Saharan African regions where Plasmodium falciparum malaria is endemic [24,25,26]. Recently, MHC alleles encoding for allotypes with functional similarities to those of HLA-B*53 and HLA-B*78 have also been suggested to play a protective role explaining the likely absence of malaria parasites in bonobos [27]. In addition, demographic processes such as population bottlenecks, genetic drift, demographic expansions or migrations shape the HLA molecular profiles by increasing or decreasing their diversity and create population structure most often highly correlated to geography [21, 28,29,30].

Whether and how MHC genetic variation persists in populations having undergone a pronounced reduction in size, either due to a founder effect or to an epidemic, is an important issue in evolutionary genetics and conservation biology [30,31,32,33,34]. Indeed, a loss of genetic variation, particularly concerning immune-related loci, may have dramatic effects on populations’ survival [33], even though a direct correlation between a lower MHC diversity and a greater susceptibility to diseases has not been demonstrated so far at a population level [35, 36]. In this context, theoretical and empirical studies investigating the relative effects of genetic drift and natural selection on MHC variability during population bottlenecks in different species have reported contrasting results, indicating either that balancing selection processes were efficient enough to maintain moderate to high MHC diversity [31, 37,38,39,40] or that demographic factors exerted stronger influence than selection on diversity [41, 42]. Additionally, the impact of selection may depend both on the timescales, e.g. selection would be able to restore diversity to pre-bottleneck levels after 40 generations [31], and on the specific MHC gene studied [38, 39, 41].

One useful approach to unravel the multiple mechanisms governing the evolution of the MHC region is to compare the diversity of homologous genes among closely related species that underwent distinct demographic histories. This is the case for humans and chimpanzees, which share a common ancestor dating back to

6–8 million years (Myr) ago [43, 44]. According to both archaeological and genetic data, anatomically modern humans (Homo sapiens) first appeared and expanded demographically in Africa between 300,000 and 200,000 years ago [45, 46]. They later dispersed, likely in small groups, across all continents where they eventually underwent secondary expansions, the most extensive ones (in Prehistoric times) occurring in the Neolithic [47, 48]. However, many human populations (most Amerindian, Oceanian and present-day hunter-gatherer and nomadic populations from different continents) did not undergo demographic expansions [49] and still live today in isolated areas where they experience little gene flow and rapid genetic drift [50]. Due to the paucity of fossil records [51], the demographic history of chimpanzee populations relies almost exclusively on molecular analyses. The latter suggest the emergence of both common chimpanzees (Pan troglodytes, P.t. hereafter) and bonobos (Pan paniscus) in Central Africa from a common ancestor

1–2 Myr ago [43, 44] but while bonobos probably remained confined within the small geographic region where they inhabit today (a narrow territory between the Congo and Kasai Rivers), common chimpanzees expanded across a wider area of equatorial Africa where they are represented today by distinct sub-species (P.t.verus in Western Africa, P.t.ellioti in Nigeria and Cameroon, P.t.troglodytes in Central Africa, and P.t.schweinfurthii in Eastern Africa), albeit mainly within a limited rainforest habitat [52,53,54].

MHC molecular data analyses indicated that both common chimpanzees and bonobos experienced a selective sweep owing to the action of a hypothesised retroviral infection that severely shrunk their population sizes (bottleneck events) [55, 56]. The first evidence comes from the observation of a reduced repertoire of allele families at the Patr-A locus compared to the HLA-A locus in humans [57], suggesting a strong selective sweep – i.e. either purifying or positive directional selection - within the chimpanzees’ MHC class I region. Indeed, whereas HLA-A alleles belong to six different allele families (A2, A10 and A19 within the A2 lineage, and A1/A3/A11/A30, A9 and A80 within the A3 lineage), all Patr-A alleles known so far are associated to the single A1/A3/A11/A30 family [57,58,59,60,61,62] and a similar observation has been reported for the Papa-A alleles [63] (Papa is the name of MHC genes in bonobo). Next, Patr- and Papa-A, −B, −C intron 2 analyses substantiated the reduced diversity observed in the Western chimpanzee (P.t.verus) and bonobo MHC class I regions as compared to HLA-A, −B, −C in humans [55, 63, 64]. In addition, microsatellite analyses in Western chimpanzees and humans revealed a reduced diversity in the Patr region in comparison to microsatellites located elsewhere in the genome [56]. Finally, chimpanzees were shown to exhibit a 95 kb deletion in the MIC region located next to locus B where the single MIC gene, which is fixed on all haplotypes, likely results from the fusion of two ancestral MICA and MICB genes still present in humans [65]. The hypothesis of a selective sweep proposed for chimpanzees finds support in the low genomic diversity found in all common chimpanzee sub-species and in bonobos, which was ascribed to a bottleneck in the ancestors of both species [44]. In addition, these genome-wide analyses also highlighted a second bottleneck occurring later (

500,000 years ago) in Western and Nigeria-Cameroon chimpanzees only (although not quite as severe for the latest), which would partially explain why P.t.verus generally displays lower molecular variation in nuclear genes compared to other chimpanzee (sub-)species [44, 66,67,68,69,70,71].

In this study, our objective is to assess whether the genetic diversity at different Patr genes, estimated by means of three different indexes, allelic richness, expected heterozygosity and nucleotide diversity, is significantly reduced in present-day Western chimpanzee as a possible response to their past bottlenecks compared to that of their HLA orthologs in human populations. The detection of a substantially reduced level of Patr diversity would be a possible indicator of depleted immunity and an additional reason to consider P.t.verus as a critically endangered subspecies [72]. Actually, we anticipate chimpanzees’ MHC diversity to be (not necessarily similar but) closer to that of small isolated, as opposed to large outbred human populations (independently of their geographical location) if demographic contractions played a major role on the MHC evolution of both species. In addition, we expect the patterns of genetic variation and linkage disequilibrium to be similar across the HLA and Patr regions if their orthologous loci evolved through analogous molecular mechanisms and were targeted by similar selective pressures in the two species. To address these issues, we analysed all the data currently available for 7 Patr genes (A, B, C, DRB1, DQA1, DQB1 and DPB1) in four P.t.verus cohorts, and we compared them to large sets of data for HLA genes (A, B, C, DRB1, DQA1, DQB1 and DPB1) data previously studied in human populations from different continents, that we also extensively reanalysed. We found marked similarities in Patr and HLA genetic diversity and linkage disequilibrium patterns, indicating highly conserved mechanisms of MHC evolution in chimpanzees and humans. We also showed that Western chimpanzees globally exhibit similar diversity levels and equivalent amounts of linkage disequilibrium to those estimated in small isolated human populations, which suggests that their past bottleneck exerted a substantial effect on the molecular diversity of Patr genes. However, as there was no difference in the MHC diversity of chimpanzees compared to human populations that likely underwent more recent, rapid genetic drift, we hypothesize that several Patr genes rapidly recovered molecular variation after their selective sweep.


29.3: Genetic Linkage - Biology

The phenomenon of permanent association of genes of a single chromosome that can be inherited in successive generations in same position and proportion without any changes or separation is called linkage.

Mendel did not notice the phenomenon of linkage because he chose characteristics controlled by genes located on different chromosomes. This phenomenon of linkage was noticed by post- Mendelian geneticists. It was firstly discovered by Bateson and Punnet (1906) while working on sweet pea (Lathyrus odoratus)in which they found two pairs of alleles did not assort independently. Sutton and Boveri first suggested linkage in 1903 when they first suggestion linkage when they propounded "Chromosomal Theory of Inheritance." The term 'Linkage' was coined by T.H. Morgan and he proposed "chromosomal theory of linkage" by working on Drosophila 1910. According to this theory, the linkage is defined as the phenomenon of inheritance of genes together and retain their parental combination even in the offspring.

Linked and unlinked genes

The genes present in the single chromosome are inherited together are called linked genes. Unlinked genes are those genes which are found on the different chromosome. Those characters which are controlled by linked genes are called linked characters.

Unlinked Genes

They are found on the same chromosome.

They show independent assortment.

Dihybrid phenotypic ratio is 9:3:3:1.

The test cross ratio in dihybrid cross is 1:1:1:1.

Linkage group

Genes situated on the chromosome are said to be linked. The genes on the single chromosome form a linkage group. A linkage group usually passes into a gamete and are inherited together. Linkage group in a cell equals to the pair of chromosomes present in the cell of an organism. But it should be noted that the number of linkage group is restricted to the haploid number of chromosomes of an organism. The total number of linked genes present in a single chromosome from the linkage group. The linkage group can be determined by:

number of linkage group= number of haploid chromosomes in an organism,

Example- In Drosophila-2n = 8&rArr n=4&rArr n= 3+xy&rArr 3+x+y&rArr 5

In human female- 2n=46&rArr n=23&rArr n=22+xx&rArr 22+x (homomeric/gametic) &rArr 23

Chromosomal Theory of Linkage-

Morgan formulated the chromosomal theory of linkage according to which-

1)Genes lie in linear order in the chromosomes and distance between them is variable.

2)The genes that are linked, stay on the same chromosome.

3)The tendency of genes to remain together in their parental combination is due to their presence on the same chromosome.

4)The strength of linkage is directly related to the distance between the linked genes on a chromosome. The closer the genes are located, stronger is the linkage.

Types of linkage

1) Complete linkage

2) Incomplete linkage

1) Complete linkage -The phenomenon in which the genes present in a single chromosome do not separate and are inherited together in the successive generations due to the absence of crossing over is called complete linkage. Hence it produces only parental combination but not non-parental ones. It is very rare in nature.

A cross between Drosophilawith gray body- normal wings [GGNN] and black body-vestigial wings [ggnn] -

The above cross produces F1 hybrids with the gray body- normal wings [GgNn]. When these F1 hybrids are crossed with the recessive parent having a black body- vestigial wings (test-cross), it produces two types of offspring in equal proportion (50% - 50%) in F2 generation. These F2 offspring resemble their grandparents.

Hence, the gray-body character is inherited with normal wings and black body character is inherited together with vestigial wings. It means these genes are linked genes and no non-parental combination are formed due to the absence of crossing over.

Fig: Complete linkage

From the above cross - F2 ratio= gray body normal wings= 50%

and, black body vestigial wings= 50%

2) Incomplete linkage -The phenomenon in which linked genes present in the same chromosome have a tendency to separate due to crossing over and forms both parental and non-parental combination in the F2generation is called incomplete linkage. It can be illustrated in maize grains.

When colored-full seed [CCFF] of maize is crossed with colorless-shrunken seed [ccff] of maize-

The above cross produces F1hybrids with coloured-full seeds [CcFf] of maize. When F1 hybrid female is crossed with recessive parent i:e colorless shrunken male, they produce both parental and non-parental combination with four phenotypes in the ratio of 1:1:1:1 i:e 1 colored-full : 1 colored-shrunken : 1 colorless-full : 1 colorless-shrunken seed. This is possible due to the incomplete linkage.

Fig: Incomplete linkage

From the cross above the F2 phenotypic ratio is = 1:1:1:1.

Significance of linkage-

The phenomenon of linkage has great significance for living organisms, because-

1) It reduces the possibility of variability in gametes.

2) The number of linkage groups is equivalent to number of chromosomes present in genome,

3) It is useful for maintaining the good characters in new variety,

4) Linked character is preserved for successive generations because linkage prevents the incidence of crossing over.

5) It doesn't permit the plant breeders to bring the desirable character in a variety,

Reasons for selectingDrosophilafor genetic studies-

The reasons for selectingDrosophilafor genetic studies are as follows-

1)Drosophilacan be cultured easily under normal condition.

2)Drosophilais harmless and inexpensive to culture. The culture medium required to rear them is also very simple.

3) A large number of Drosophilacan be accommodated in a small space.

4) Progeny produced after each mating is large.

5) It breeds throughout the year. Its life cycle is short and completed in 10-12 days so that the results of controlled breeding are quickly available.

6) The number of chromosomes is only four pairs and all are of different size and shape. Chromosomes II, III, and IV are autosomes while the chromosome 'I' is sex chromosome. Female has XX and male has XY, Y being characteristically J-shaped. It is, therefore, easy to identify and study each chromosome.

Keshari, Arvind K. and Kamal K. Adhikari. A Text Book of Higher Secondary Biology(Class XII). 1st. Kathmandu: Vidyarthi Pustak Bhandar, 2015.

Mehta, Krishna Ram. Principle of biology. 2nd edition. Kathmandu: Asmita, 2068,2069.

Jorden, S.L. principle of biology. 2nd edition . Kathmandu: Asmita book Publication, 2068.2069.

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Things to remember
  • The phenomenon of permanent association of genes of a single chromosome that can be inherited in successive generations in same position and proportion without any changes or separation is called linkage.
  • Linkage was firstly discovered by Bateson and Punnet (1906) while working on sweet pea (Lathyrus odoratus)in which they found two pairs of alleles did not assort independently.
  • Sutton and Boveri first suggested linkage in 1903 when they first suggestion linkage when they propounded "Chromosomal Theory of Inheritance."
  • The term 'Linkage' was coined by T.H. Morgan and he proposed "chromosomal theory of linkage" by working on Drosophila 1910.
  • The genes on the single chromosome form a linkage group.
  • The phenomenon in which the genes present in a single chromosome do not separate and are inherited together in the successive generations due to the absence of crossing over is called complete linkage.
  • The phenomenon in which linked genes present in the same chromosome have a tendency to separate due to crossing over and forms both parental and non-parental combination in the F2generation is called incomplete linkage.
  • It includes every relationship which established among the people.
  • There can be more than one community in a society. Community smaller than society.
  • It is a network of social relationships which cannot see or touched.
  • common interests and common objectives are not necessary for society.

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