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Page Y Chr 2004 “Rethinking the Rotting Y Chromosome” Sex Chromosome Evolution: Y as Rotting X SRY SRY SRY A pair of X Y X Y X Y autosomes 1 Nature 415, 963 (2002) The future of sex R. John Aitken and Jennifer A. Marshal Graves “The Y chromosome is particularly vulnerable … because it is not a matching partner for the X chromosome, so it cannot retrieve lost genetic information by recombination…. The original Y chromosome contained around 1,500 genes, but during the ensuing 300 million years all but about 50 were inactivated or lost…. At the present rate of decay, the Y chromosome will self-destruct in around 10 million years.” 2 The Human Y Chromosome: An early map Testis Determining Factor (TDF) Three Stooges Appreciation (Curly Stimulation Factor, CSF) Channel Flipping (FLP) p Catching And Throwing (BLZ1) CEN Self-confidence (BLZ2) (unlinked to ability) Ability to remember and tell jokes (GOT1) q Sports Page (BUD-E) Addiction to death & destruction movies (T-2) Air Guitar (RIF) Ability to Identify Aircraft (DC-10) Preadolescent fascination with Arachnida/Reptilia (MOM-4U) Spitting (P2E) Sitting on toilet reading (linked to Sports Page) Inability to express affection over the phone (ME-2) Selective hearing loss (HUH) heterochromatin Total lack of recall for dates (OOPS) The MSY, the Male-Specific Region of the Human Y Chromosome Euchromatin 23 Mb 1% of human genome Heterochromatin p q The MSY differs from other nuclear chromosomes: - specific to one sex - no crossing over 3 Spermatogenic Specialization of MSY Revealed by Genomics Analyses • DNA sequence of chromosome • Catalog of genes • Y deletions spermatogenic failure Tomoko Helen Kuroda- Skaletsky Kawaguchi David Page 4 MSY Euchromatin: Three Sequence Classes X-transposed (99% X-Y identity) X-degenerate Ampliconic p q Y-specific repeated blocks (amplicons) comprise one third of MSY’s euchromatic DNA Considerations in Sequencing the Euchromatic MSY 1. Y-specific repeats ("amplicons") of unknown number, structure, and unit length may account for 1/3 of euchromatic MSY Vollrath et al., Science 258: 52 (1992) Foote et al., Science 258: 60 (1992) 2. Amplicon-rich regions of MSY contain genes; should not be ignored Reijo et al., Nature Genet. 10: 383 (1995) Lahn & Page, Science 278: 675 (1997) 3. Case of DAZ genes suggested that MSY amplicons might be >99% (even 99.9%) identical in DNA sequence Saxena et al., Nature Genet. 14: 292 (1996) Saxena et al., Genomics 67: 256 (2000) 4. Polymorphic differences between Y chromosomes in two men (0.1%) might approximate sequence divergence among amplicons within one Y chromosome 5 Disentangling Amplicon Copies Differing by as Little as 1 per 10,000 bp one chromosome no polymorphism BAC mapping BAC sequencing (BACs comparable to amplicons in length) big overlaps between sequenced BACs detect map assembly errors no tolerance for sequence discrepancies between overlapping BACs accurate final assembly (~1 error / Mb) Ampliconic Sequences Defined by High Similarity to Other MSY Sequences 100 100 75 75 Intrachromosomal 50 50 similarity (% identity) 1 Mb 6 18 Single-CopyMSYGeneswithXHomologs Most oftheseX-Ygenesareubiquitouslyexpressed. RBMY XKRY HSFY TSPY BPY2 CDY VCY PRY DAZ SRY All arelocatedoutsidetheampliconicregions. RPS4Y ZFY 60 Members,AllLocatedinAmplicons 9 Testis-Speci TGIF2LY PCDH11Y AMELY TBL1Y PRKY fi c MSYGeneFamilies: USP9Y DBY UTY TMSB4Y NLGN4Y CYorf15A CYorf15B SMCY EIF1AY RPS4Y2 7 And most of the testis genes are in palindromes... Structure of an MSY Palindrome 99.9% - 99.99% identity 1 or more testis genes 1 or more testis genes testis more or 1 up to 1.5 million bp 8 8 Palindromes and 1 Inverted Repeat Comprise 25% of MSY Euchromatin VCY XKRY HSFY RBMY PRY CDY BPY2 DAZ Yp Yq 867 54IR2 32 1 DNA Sequence Dot Plot: An Ampliconic Region vs. Itself window: 500 bp stringency: 500 bp P1 P3 P2 cen qter 1 Mb 9 Uniform AZFc Deletions Detected in Azoospermic Males cen qter t2 g1 r4 t1 r1 r2 r3 u1 b1 b3 y1 y2 b4 u2 b2 u3 g2 g3 1 Mb 3.5 Mb AZFc Deletions Caused by Homologous Recombination Between 229 kb Direct Repeats window: 500 bp stringency: 500 bp 99.9% P1 1 Mb P3 P 2 cen qter recombination targets 10 In silico Fractionation of MSY Euchromatic DNA 0.20 0.20 0.15 0.15 0.10 0.10 sequence 0.05 0.05 Fraction of euchromatic 0.00 0.00 90 95 98 70 80 99 99.9 100.0 Intrachromosomal similarity (% identity) 30% of euchromatin displays > 99.9% identity to other MSY sequences Intact Testis Genes Located in 99.9% Fraction of MSY; Pseudogenes Located Throughout # of intact genes with # of pseudogenes with 99.9% identity to other MSY < 99.9% 99.9% < 99.9% sequences DAZ 4 0 0 0 CDY 4 0 17 4 PRY 2 0 4 0 BPY2 3 0 many many RBMY 6 0 6 17 HSFY 2 0 0 0 VCY 2 0 0 0 XKRY 2 0 6 0 Total 25 0 >33 >21 11 > 99.9% arm-to-arm identity in MSY palindromes implies either: 1) very recent origin (~100,000 yrs ago) or 2) ongoing homogenization via nonreciprocal recombination Do the “same” (orthologous) palindromes exist on chimp Y chromosome? Gene Conversion - a result of homologous recombination; initiated by double strand breaks - nonreciprocal transfer of info from one DNA duplex to another (as opposed to crossing over, which is reciprocal) - between homologs, sister chromatids, or repeats on a single chromosome - can occur in meiosis or mitosis 12 Concerted Evolution of MSY Palindrome Arms 0.021 % 0.028 % 1.44 % Human Chimpanzee Arm-to-Arm Gene Conversion in our Species T T C T C C M34 M117 M58 M123 M78 M81 M9M922 M134 M50 pSRY373 USP9Y+3636 SRY10831 DYS271 M35 M67M6 7 M1M122 M82 M122 M119 M95 M76 M124 M3 M173 M118 M75 YAPPN2 M172 M52 M175 USP9Y+3178 M20 M4 M45 M13 M51 M9 M170 p12f M69 M9 M144 M109 M112 YAP RPS4Y711 M89 M32 M14 M60 M168 M91 SRY10831 C T 13 MSY Gene Conversion - 30% of euchromatic DNA - maintains > 99.9 % DNA identity - approx. 600 bp per generation - molecular mechanism unknown - recombination partners in inverted orientation (e.g., palindromes) - 8 of 9 testis-specific gene families (2, 4, 6 … rule) - speculation: preserves gene function in absence of sex (ual recombination) Two Forms of Productive Recombination in Human Y Chromosome Male-specific region Yp Yq 1. X-Y crossing-over in pseudoautosomal regions 2. Y-Y gene conversion in portions of MSY that exhibit >99.9% intrachromosomal identity 14 Old and New Understandings of the MSY ~76 protein-coding genes genetic wasteland 27 distinct proteins; spermatogenic specialization many genes imported (from merely a rotting copy of autosomes and X) during primate an ancient autosome evolution; gene amplification gene-rich palindromes of full of junky repeats unprecedented scale + precision no productive recombination gene conversion method of all genes disintegrating preserving gene integrity? (Muller’s Ratchet) Primates Carnivores H. sapiens Marsupials Rodents Monotremes Birds Amphibians Reptiles Fishes Vertebrate genomes: Chordata Completed, in progress or pending 15.
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