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PMID: 24759411 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators.

Nature ·Vol. 508 ·No. 7497 ·2014-04-24 ·Pages 494-9

Bellott DW, Hughes JF, Skaletsky H, Brown LG, Pyntikova T, Cho TJ, Koutseva N, Zaghlul S, Graves T, Rock S, Kremitzki C, Fulton RS, Dugan S, Ding Y, Morton D, Khan Z, Lewis L, Buhay C, Wang Q, Watt J, Holder M, Lee S, Nazareth L, Alföldi J, Rozen S, Muzny DM, Warren WC, Gibbs RA, Wilson RK, Page DC

Abstract

The human X and Y chromosomes evolved from an ordinary pair of autosomes, but millions of years ago genetic decay ravaged the Y chromosome, and only three per cent of its ancestral genes survived. We reconstructed the evolution of the Y chromosome across eight mammals to identify biases in gene content and the selective pressures that preserved the surviving ancestral genes. Our findings indicate that survival was nonrandom, and in two cases, convergent across placental and marsupial mammals. We conclude that the gene content of the Y chromosome became specialized through selection to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly expressed regulators of transcription, translation and protein stability. We propose that beyond its roles in testis determination and spermatogenesis, the Y chromosome is essential for male viability, and has unappreciated roles in Turner's syndrome and in phenotypic differences between the sexes in health and disease.

MeSH Terms
Animals Chromosomes, Human, X/genetics Chromosomes, Human, Y/genetics Disease Evolution, Molecular Female Gene Dosage/genetics Gene Expression Regulation Health Humans Male Mammals/genetics Marsupialia/genetics Molecular Sequence Annotation Molecular Sequence Data Protein Biosynthesis/genetics Protein Stability Selection, Genetic/genetics Sequence Homology Sex Characteristics Spermatogenesis/genetics Testis/metabolism Transcription, Genetic/genetics Turner Syndrome/genetics X Chromosome/genetics Y Chromosome/genetics
Authors & Affiliations
30 authors, click to expand affiliations / ORCID
Bellott Daniel W
Whitehead Institute, Howard Hughes Medical Institute, & Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Hughes Jennifer F
Whitehead Institute, Howard Hughes Medical Institute, & Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Skaletsky Helen
Whitehead Institute, Howard Hughes Medical Institute, & Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Brown Laura G
Whitehead Institute, Howard Hughes Medical Institute, & Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Pyntikova Tatyana
Whitehead Institute, Howard Hughes Medical Institute, & Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Cho Ting-Jan
Whitehead Institute, Howard Hughes Medical Institute, & Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Koutseva Natalia
Whitehead Institute, Howard Hughes Medical Institute, & Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Zaghlul Sara
Whitehead Institute, Howard Hughes Medical Institute, & Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Graves Tina
The Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
Rock Susie
The Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
Kremitzki Colin
The Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
Fulton Robert S
The Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
Dugan Shannon
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Ding Yan
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Morton Donna
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Khan Ziad
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Lewis Lora
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Buhay Christian
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Wang Qiaoyan
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Watt Jennifer
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Holder Michael
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Lee Sandy
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Nazareth Lynne
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Alföldi Jessica
Whitehead Institute, Howard Hughes Medical Institute, & Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Rozen Steve
Whitehead Institute, Howard Hughes Medical Institute, & Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Muzny Donna M
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Warren Wesley C
The Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
Gibbs Richard A
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Wilson Richard K
The Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
Page David C
Whitehead Institute, Howard Hughes Medical Institute, & Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
References (66)
66 references, click to expand
  1. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men.
    Nat Genet. 2001 Nov;29(3):279-86 PMID: 11687796
  2. A proposed path by which genes common to mammalian X and Y chromosomes evolve to become X inactivated.
    Nature. 1998 Aug 20;394(6695):776-80 PMID: 9723615
  3. The distribution of chromosomal genotypes associated with Turner's syndrome: livebirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosaicism.
    Hum Genet. 1983;64(1):24-7 PMID: 6683706
  4. Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1.
    Am J Hum Genet. 1998 Dec;63(6):1757-66 PMID: 9837829
  5. The DNA sequence of the human X chromosome.
    Nature. 2005 Mar 17;434(7031):325-37 PMID: 15772651
  6. Independent specialization of the human and mouse X chromosomes for the male germ line.
    Nat Genet. 2013 Sep;45(9):1083-7 PMID: 23872635
  7. Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype-phenotype correlation.
    Eur J Hum Genet. 2010 Mar;18(3):330-5 PMID: 19826449
  8. Del (X)(p21.2) in a mother and two daughters with variable ovarian function.
    Clin Genet. 1997 Oct;52(4):235-9 PMID: 9383030
  9. Retarded development of XO conceptuses during early pregnancy in the mouse.
    J Reprod Fertil. 1983 Jul;68(2):387-93 PMID: 6864654
  10. UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program.
    Dev Cell. 2012 Jan 17;22(1):25-37 PMID: 22192413
  11. Functional equivalence of human X- and Y-encoded isoforms of ribosomal protein S4 consistent with a role in Turner syndrome.
    Nat Genet. 1993 Jul;4(3):268-71 PMID: 8358435
  12. Characterising and predicting haploinsufficiency in the human genome.
    PLoS Genet. 2010 Oct 14;6(10):e1001154 PMID: 20976243
  13. Strict evolutionary conservation followed rapid gene loss on human and rhesus Y chromosomes.
    Nature. 2012 Feb 22;483(7387):82-6 PMID: 22367542
  14. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif.
    Nature. 1990 Jul 19;346(6281):240-4 PMID: 1695712
  15. Chromosome-wide profiling of X-chromosome inactivation and epigenetic states in fetal brain and placenta of the opossum, Monodelphis domestica.
    Genome Res. 2014 Jan;24(1):70-83 PMID: 24065774
  16. Remarkably little variation in proteins encoded by the Y chromosome's single-copy genes, implying effective purifying selection.
    Am J Hum Genet. 2009 Dec;85(6):923-8 PMID: 20004767
  17. Human DDX3Y, the Y-encoded isoform of RNA helicase DDX3, rescues a hamster temperature-sensitive ET24 mutant cell line with a DDX3X mutation.
    Exp Cell Res. 2004 Oct 15;300(1):213-22 PMID: 15383328
  18. Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate.
    Hum Genet. 2013 May;132(5):537-52 PMID: 23354975
  19. Copy-number gains of HUWE1 due to replication- and recombination-based rearrangements.
    Am J Hum Genet. 2012 Aug 10;91(2):252-64 PMID: 22840365
  20. XO monosomy is associated with reduced birthweight and lowered weight gain in the mouse.
    J Reprod Fertil. 1983 Jul;68(2):381-5 PMID: 6864653
  21. Update on activities at the Universal Protein Resource (UniProt) in 2013.
    Nucleic Acids Res. 2013 Jan;41(Database issue):D43-7 PMID: 23161681
  22. Evolutionary dynamics of gene and isoform regulation in Mammalian tissues.
    Science. 2012 Dec 21;338(6114):1593-9 PMID: 23258891
  23. A cytogenetic and molecular study of a series of 45,X fetuses and their parents.
    J Med Genet. 1991 Mar;28(3):151-5 PMID: 1675683
  24. The MECP2 duplication syndrome.
    Am J Med Genet A. 2010 May;152A(5):1079-88 PMID: 20425814
  25. Evolutionary history of novel genes on the tammar wallaby Y chromosome: Implications for sex chromosome evolution.
    Genome Res. 2012 Mar;22(3):498-507 PMID: 22128133
  26. Human and mouse amelogenin gene loci are on the sex chromosomes.
    Genomics. 1989 Feb;4(2):162-8 PMID: 2737677
  27. A study of females with deletions of the short arm of the X chromosome.
    Hum Genet. 1998 May;102(5):507-16 PMID: 9654198
  28. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes.
    Nature. 2003 Jun 19;423(6942):825-37 PMID: 12815422
  29. Large-scale gene function analysis with the PANTHER classification system.
    Nat Protoc. 2013 Aug;8(8):1551-66 PMID: 23868073
  30. Del(X)(p21.1) in a mother and two daughters: genotype-phenotype correlation of Turner features.
    Hum Genet. 2000 Mar;106(3):306-10 PMID: 10798359
  31. Cytogenetic and molecular analysis of sex-chromosome monosomy.
    Am J Hum Genet. 1988 Apr;42(4):534-41 PMID: 2894760
  32. Nonrandom gene loss from the Drosophila miranda neo-Y chromosome.
    Genome Biol Evol. 2011;3:1329-37 PMID: 21987387
  33. The amelogenin loci span an ancient pseudoautosomal boundary in diverse mammalian species.
    Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5258-63 PMID: 12672962
  34. Deletion of the short arm of the X chromosome: a hereditary form of Turner syndrome.
    Eur J Pediatr. 1992 Dec;151(12):893-4 PMID: 1473542
  35. Molecular cytogenetic analysis of a familial interstitial deletion Xp22.2-22.3 with a highly variable phenotype in female carriers.
    Am J Med Genet A. 2006 Mar 15;140(6):604-10 PMID: 16470742
  36. The DAZ gene cluster on the human Y chromosome arose from an autosomal gene that was transposed, repeatedly amplified and pruned.
    Nat Genet. 1996 Nov;14(3):292-9 PMID: 8896558
  37. Building human genome maps with radiation hybrids.
    J Comput Biol. 1997 Winter;4(4):487-504 PMID: 9385541
  38. Dosage-sensitive X-linked locus influences the development of amygdala and orbitofrontal cortex, and fear recognition in humans.
    Brain. 2003 Nov;126(Pt 11):2431-46 PMID: 12958079
  39. Four evolutionary strata on the human X chromosome.
    Science. 1999 Oct 29;286(5441):964-7 PMID: 10542153
  40. Ensembl 2014.
    Nucleic Acids Res. 2014 Jan;42(Database issue):D749-55 PMID: 24316576
  41. The X chromosome of monotremes shares a highly conserved region with the eutherian and marsupial X chromosomes despite the absence of X chromosome inactivation.
    Proc Natl Acad Sci U S A. 1990 Sep;87(18):7125-9 PMID: 2402495
  42. A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes.
    Nature. 1990 Jul 19;346(6281):245-50 PMID: 2374589
  43. A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability.
    Am J Hum Genet. 2012 Oct 5;91(4):694-702 PMID: 23000143
  44. Sex chromosomes: how X-Y recombination stops.
    Curr Biol. 2003 Aug 19;13(16):R641-3 PMID: 12932341
  45. A high-resolution radiation hybrid map of rhesus macaque chromosome 5 identifies rearrangements in the genome assembly.
    Genomics. 2008 Oct;92(4):210-8 PMID: 18601997
  46. TimeTree: a public knowledge-base of divergence times among organisms.
    Bioinformatics. 2006 Dec 1;22(23):2971-2 PMID: 17021158
  47. Familial deletion within NLGN4 associated with autism and Tourette syndrome.
    Eur J Hum Genet. 2008 May;16(5):614-8 PMID: 18231125
  48. PAML: a program package for phylogenetic analysis by maximum likelihood.
    Comput Appl Biosci. 1997 Oct;13(5):555-6 PMID: 9367129
  49. Interchromosomal gene conversion as a possible mechanism for explaining divergence patterns of ZFY-related genes.
    J Mol Evol. 1992 Aug;35(2):181-3 PMID: 1501256
  50. Functional coherence of the human Y chromosome.
    Science. 1997 Oct 24;278(5338):675-80 PMID: 9381176
  51. The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region.
    Hum Mol Genet. 1998 Mar;7(3):489-99 PMID: 9467009
  52. Structural variation on the short arm of the human Y chromosome: recurrent multigene deletions encompassing Amelogenin Y.
    Hum Mol Genet. 2007 Feb 1;16(3):307-16 PMID: 17189292
  53. Abundant gene conversion between arms of palindromes in human and ape Y chromosomes.
    Nature. 2003 Jun 19;423(6942):873-6 PMID: 12815433
  54. Oocyte depletion in XO mice and their XX sibs from 12 to 200 days post partum.
    J Reprod Fertil. 1981 Jan;61(1):207-12 PMID: 7452619
  55. Global survey of escape from X inactivation by RNA-sequencing in mouse.
    Genome Res. 2010 May;20(5):614-22 PMID: 20363980
  56. The temporal dynamics of processes underlying Y chromosome degeneration.
    Genetics. 2008 Jul;179(3):1513-25 PMID: 18562655
  57. Conservation of Y-linked genes during human evolution revealed by comparative sequencing in chimpanzee.
    Nature. 2005 Sep 1;437(7055):100-3 PMID: 16136134
  58. Rewirable gene regulatory networks in the preimplantation embryonic development of three mammalian species.
    Genome Res. 2010 Jun;20(6):804-15 PMID: 20219939
  59. X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner.
    Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):13004-9 PMID: 22826230
  60. Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content.
    Nature. 2010 Jan 28;463(7280):536-9 PMID: 20072128
  61. PANTHER: a library of protein families and subfamilies indexed by function.
    Genome Res. 2003 Sep;13(9):2129-41 PMID: 12952881
  62. X-inactivation profile reveals extensive variability in X-linked gene expression in females.
    Nature. 2005 Mar 17;434(7031):400-4 PMID: 15772666
  63. MUSCLE: multiple sequence alignment with high accuracy and high throughput.
    Nucleic Acids Res. 2004 Mar 19;32(5):1792-7 PMID: 15034147
  64. UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development.
    PLoS Genet. 2012 Sep;8(9):e1002964 PMID: 23028370
  65. The Drosophila developmental gene fat facets has a human homologue in Xp11.4 which escapes X-inactivation and has related sequences on Yq11.2.
    Hum Mol Genet. 1996 Nov;5(11):1695-701 PMID: 8922996
  66. Convergent evolution of chicken Z and human X chromosomes by expansion and gene acquisition.
    Nature. 2010 Jul 29;466(7306):612-6 PMID: 20622855
Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature13206
Published
2014-04-24
Pages
494-9
Language
English
Region
England
NLM ID
0410462
PMCID
PMC4139287
Subset
IM
Grants
Howard Hughes Medical Institute · United States
NCRR NIH HHS · P51 RR013986 · United States
NHGRI NIH HHS · U54 HG003079 · United States
NHGRI NIH HHS · U54 HG003273 · United States
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GENBANK
FJ526999, FJ527000, FJ527001, FJ527002, FJ527003, FJ527004, FJ527005, FJ527006, FJ527007, FJ527008, FJ627275, FJ627276, FJ627278, FJ659845, FJ959389, GQ253467, GQ253468, GQ253469, GQ253470, GQ253471, GQ253472, GQ253473, GQ253474, GQ253475, GQ338825, GU304599, GU304600, GU304601, GU304602, GU304603, GU304606, GU304607, JF487792, JF487793, JF487794, JF487795, JF827151, JF827152, JN086997, JN585955, JN585956, JQ313990, JQ313991, JQ313992
Corrections
ErratumIn
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CommentIn
PMID: 24759407
External Links
PubMed source DOI: 10.1038/nature13206 PMC Full Text View journal details
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