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High Mutation Rates Have Driven Extensive Structural Polymorphisms Among Human Y Chromosomes

High Mutation Rates Have Driven Extensive Structural Polymorphisms Among Human Y Chromosomes. Matthew Byrnes. Outline. The Y Chromosome and its Apparent Problems Origins of the Y chromosome Is the Human Y chromosome degenerating perniciously? Homo vs. Pan Y chromosome studies

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High Mutation Rates Have Driven Extensive Structural Polymorphisms Among Human Y Chromosomes

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  1. High Mutation Rates Have Driven Extensive Structural Polymorphisms Among Human Y Chromosomes Matthew Byrnes

  2. Outline • The Y Chromosome and its Apparent Problems • Origins of the Y chromosome • Is the Human Y chromosome degenerating perniciously? • Homo vs. Pan Y chromosome studies • High Mutation Rates in Human Y Chromosome • Repping et al.(2006) • Distal-Yq heterochromatin and IR3/IR3 • TSPY and AZFc • Conclusions and Summary

  3. Evolution of the Y Chromosome • X and Y diverged from autosomes of mammalian ancestors ca. 300MYA • Differentiation of X and Y only occurred after recombination suppression • There are 19 homologous genes on both the X and Y chromosomes • Located on tip of short arm in X and in 4 contiguous blocks. But are fragmented across length of Y. • Attributed to four major inversions on the Y chromosome. Prevented recombination of X-Y

  4. ca. 5% of Y is capable of recombining with X. These areas are known as pseudoautosomal regions(PAR) located at telomeres.The other 95% is known as the male-specific region(MSY). • MSY contains 78 genes which code for 27 distinct proteins. • MSY split into three euchromatic classes;1 • X-transposed region • X-degenerate region • Ampliconic region

  5. X-transposed region • Only 2 genes, almost identical with Xq21, a band on the long arm of the X chromosome • Caused by an eponymous transposition ca. 3MYA after divergence with chimpanzees • Large inversion within MSY short arm cleaved the region into two non-contiguous segments (total of 3.4Mb in length) • Do not cross over during male meiosis unlike PARs.

  6. X-degenerate region • Replete with single-copy genes or pseudogene homologues of 27 X-linked genes • Possible remnants of an ancient autosome,homology indicative of coevolution of both X and Y from autosome. • e.g Y-linked genes RPS4Y1 and RPS4Y2 are full length homologues of X-linked gene RPS4X, which encode two different, full-length isoforms of ribosomal protein S4. • Contains 16 of 27 protein families in MSY;including the sex-determining gene SRY and all 12 of the ubiquitously expressed genes

  7. Summary of X-transposed and X-degenerate protein families

  8. Ampliconic region • By far constitutes more of the MSY than the other two classes(10.2Mb) and shows a significantly higher gene density than the other two regions • Consists largely of 99.9% similar sequences which maintain identity over 10-100Kb • Originated from amplification of X-degenerate genes (RBMY, VCY) • transposition and amplification of autosomal genes (DAZ from chromosome 3) • And retroposition and amplification of autosomal genes (CDY).

  9. Ampliconic region • Each of these genes has been amplified, one of them (TSPY) has multiplied itself 35 times. • 9 of the distinct protein families are expressed exclusively in testes

  10. Summary of Ampliconic protein families

  11. Is the Y Chromosome Degenerating Perniciously? • Clonal transmission paternally poses a problem for Y chromosome • Chromosome is greatly emaciated, ca. 30% and less than 10% length and gene content of X chromosomes • On this notion,it has been proposed that the Y chromosome will be bereft of functional genes in 10MY(impending demise hypothesis) • Contemporaneously, peers proposed integrity of Y chromosome is maintained.1

  12. Is the Y Chromosome Degenerating Perniciously? • Human ampliconic regions consist of 8 v.large palindromic sequences(9kb-1.45Mb) • Atleast 6 of these arose before divergence with Pan • Paired arms of each palindrome separated by spacer region(2-170kb) • Proposed that integrity of palindromic sequences is maintained by gene conversion between two arms of the same palindromic region2 • Found to be true,gene conversion confirmed by studies of P1.

  13. Is the Y Chromosome Degenerating Perniciously? • Gene conversion acts at a slow rate. Balanced between rates of mutations that cause differences between arms. • Indicates that process may not be driven by selective constraints, but rather a weak direction bias which favours preservation of original sequences.(at least in humans) • But what about X-degenerate genes?

  14. Is the Y Chromosome Degenerating Perniciously? • No gene conversion takes place in X-degenerate regions. So extensive gene decay is expected • 16 X-degenerate and 11 pseudogenes both present in chimpanzees and humans • Therefore, none or little gene decay has occurred in human lineage since divergence with Pan. • Functional proteins exhibit less interspecies divergence(Homo vs pan) than intronic DNA sequences • Suggests stabilizing selection is imperative to maintaining functionality of human X-degenerate regions

  15. Homo vs Pan Y Chromosome Studies • In significant contrast, pernicious X-degenerate gene decay was prevalent in chimpanzee • Of the 8 genes found to have >1.0% divergence, 5 had undergone truncations, which was either caused by splice-site disruption, or expression of stop codons. • e.g USP9Y is vital for spermatogenesis in humans,but in Pan, it only codes for a 675 amino acid chain(cf.2555) • TMSB4Y (ubiquitous in humans) is not transcriptionally active at all. • Both differ by negligible differences in humans

  16. Homo vs Pan Y Chromosome Studies • Why have chimpanzees suffered gene decay severely, and humans negligibly? • Strong positive selection at another locality on Y? (genetic hitchhiking) • Natural selection acts on Y as a unit,as it has nothing else with which to recombine. • Deleterious mutations can be selected until fixation has occurred by linkage to beneficial mutations on other Y-linked genes

  17. Homo vs Pan Y Chromosome Studies • Ampliconic regions bear many testes-restricted genes • These play a vital role in spermatogenesis and spermatogenic failure, therefore these regions may be under intense selection pressure • Especially in taxa such as Pan which exhibit a complex mating system,mainly promiscuity. This gives rise to intense sperm competition • Monogamy, the prevailing strategy in humans, may allow for higher preservation of testes-restricted genes

  18. High Mutation Rates in Human Y ChromosomeRepping et al.(2006) • Use of ampliconic DNA sequences to determine causes of frequently recurring polymorphisms in Human male genealogy. • Are these polymorphisms recurrent independent mutations are do they originate from a single ancestor? • How are these polymorphisms governed? And what effect does natural selection have on these areas?

  19. High Mutation Rates in Human Y Chromosome • 47 chromosomes were collected, each representing a major branch of global diversity and major genealogical lineages • 9 categories of potential structural variation were investigated. And four of these showed sufficient variation to be further considered • Minimum-mutation histories and lower bound mutation rates over 52,000 generations were calculated • Distal-Yq heterochromatin • IR3/IR3 • TSPY • AZFc

  20. Regions of Y chromosome and conserved elements in Pan

  21. Distal-Yq heterochromatin • Showed large-scale length variation (29%-54% of the length of metaphase Y) • Consists of low-complexity sequences in tandem arrays • Distinct lengths must be due to multiple mutations • >12 large-scale changes equate to a rate of >2.3 X 10-4 per father-to-son transmission

  22. IR3/IR3 • Was inverted in proximal Yp in 16 of the 47 chromosomes • 3.6Mb inversion • Attributed to ectopic homologous recombination • 12 independent inversion events • >2.3 X 10-4 per father-to-son transmission (same as Yq, why is this so?)

  23. TSPY • Testes-specific protein Y-linked • Often expressed in testicular cancer • Showed large scale length variation. Ranged in size from 0.47Mb-1.3Mb • Highly similar 20.4Kb repeat units of gene and transcription factor • Result of multiple mutations

  24. TSPY • >23 changes in length >4.4 X 10-4 per father-to-son transmission • Specimens who displayed frequent changes also showed limited copy number variation.

  25. AZFc • Highest mutation rates(20 rearrangements and mutation rate of 3.8X 10-4) . Higher variation of copy number (does this correspond with significant mutations in this region?) • Very important as it bears many testes-specific genes • Many common deletions result in large sections of AZFc being removed • b2/b4 deletion removes entire region most common cause of spermatogenic failure

  26. AZFc • gr/gr mutation removes 1.6Mb, it has arose 14 times independently in human genealogy. • And as deleterious mutations are usually not able to become polymorphic this is an indicator of haploid selection being in balance with homologous recombination • b2/b3 similar to gr/gr, does not delete full copies on genes, and retains some copies.4,5 • Are ampliconic regions so duplicated to withstand intense natural selection? • Are these deleterious mutations selected in conjunction with other Y-linked genes with positive effects on fitness?

  27. Conclusions • Natural selection acts on Y in a v.different way to autosomes,and selects it as one unit. This allows for different kinetics which must be further elucidated. • High duplication in the MSY allows many functional genes to be retained by homologous recombination • Direct and indirect natural selection on certain genetic units play in integral role • Natural selection may help preserving vital spermatogenic genes by exerting a stabilizing selection on gene copy variance • Contemporary evidence points away from impending demise hypothesis for humans.

  28. References • 1.Helen Skaletsky et al(2003) The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. NATURE VOL 423 www.nature.com/nature • 2.Jennifer F. Hughes, Helen Skaletsky et al (2005) Conservation of Y-linked genes during human evolution revealed by comparative sequencing in chimpanzee. Nature vol 437 • 3.Repping et al(2006)High mutation rates have driven extensive structural polymorphism among human Y chromosomes.Nature Genetics.Advanced online publication • 4.Reppinget al.(2004)A family of human Y chromosomes has dispersed throughout northern Eurasia despite a 1.8-Mb deletion in the azoospermia factor c region. Genomics vol 83 1046–1052 • 5.Repping et.al(2003) Polymorphism for a 1.6Mb deletion of human Y chromosome through balance between recurrent mutation and haploid selection.Nature genetics.vol 35 3

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