Ohnologs in the human genome are dosage balanced and frequently associated with disease

About 30% of protein-coding genes in the human genome are related through two whole genome duplication (WGD) events. Although WGD is often credited with great evolutionary importance, the processes governing the retention of these genes and their biological significance remain unclear. One increasingly popular hypothesis is that dosage balance constraints are a major determinant of duplicate gene retention. We test this hypothesis and show that WGD-duplicated genes (ohnologs) have rarely experienced subsequent small-scale duplication (SSD) and are also refractory to copy number variation (CNV) in human populations and are thus likely to be sensitive to relative quantities (i.e., they are dosage-balanced). By contrast, genes that have experienced SSD in the vertebrate lineage are more likely to also display CNV. This supports the hypothesis of biased retention of dosage-balanced genes after WGD. We also show that ohnologs have a strong association with human disease. In particular, Down Syndrome (DS) caused by trisomy 21 is widely assumed to be caused by dosage effects, and 75% of previously reported candidate genes for this syndrome are ohnologs that experienced no other copy number changes. We propose the remaining dosage-balanced ohnologs on chromosome 21 as candidate DS genes. These observations clearly show a persistent resistance to dose changes in genes duplicated by WGD. Dosage balance constraints simultaneously explain duplicate gene retention and essentiality after WGD.

[1]  O. Jaillon,et al.  Gene loss and evolutionary rates following whole-genome duplication in teleost fishes. , 2006, Molecular biology and evolution.

[2]  Dean Nizetic,et al.  An Aneuploid Mouse Strain Carrying Human Chromosome 21 with Down Syndrome Phenotypes , 2005, Science.

[3]  C. Sommer,et al.  Trisomy 21 and Down syndrome: a short review. , 2008, Brazilian journal of biology = Revista brasleira de biologia.

[4]  J. Raes,et al.  Modeling gene and genome duplications in eukaryotes. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  S. Antonarakis,et al.  Gene expression from the aneuploid chromosome in a trisomy mouse model of down syndrome. , 2004, Genome research.

[6]  R. Veitia.  Paralogs in Polyploids: One for All and All for One? , 2005, The Plant Cell Online.

[7]  K. Yamakawa,et al.  Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome. , 2004, Human molecular genetics.

[8]  Andreas Prlic,et al.  Ensembl 2007 , 2006, Nucleic Acids Res..

[9]  J. Delabar,et al.  Molecular Mapping of Twenty-Four Features of Down Syndrome on Chromosome 21 , 1993, European journal of human genetics : EJHG.

[10]  Iuliana Ionita-Laza,et al.  Genetic association analysis of copy-number variation (CNV) in human disease pathogenesis. , 2009, Genomics.

[11]  A. Hershey,et al.  Blood expression profiles for tuberous sclerosis complex 2, neurofibromatosis type 1, and down's syndrome , 2004, Annals of neurology.

[12]  S. Dobrin,et al.  Candidate gene analysis of 21q22: Support for S100B as a susceptibility gene for bipolar affective disorder with psychosis , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[13]  K. Hokamp,et al.  The complex relationship of gene duplication and essentiality. , 2009, Trends in genetics : TIG.

[14]  David L Robertson,et al.  All duplicates are not equal: the difference between small-scale and genome duplication , 2007, Genome Biology.

[15]  X. Estivill,et al.  Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability , 2007, Nature Reviews Genetics.

[16]  Alan F. Scott,et al.  Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders , 2002, Nucleic Acids Res..

[17]  J T Richtsmeier,et al.  Parallels of craniofacial maldevelopment in down syndrome and Ts65Dn mice , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[18]  J. D. Niswander.  Cranial morphology in Down's syndrome. A comparative roentgenencephalometric study in adult males. , 1967 .

[19]  S. South,et al.  Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of down syndrome. , 2004, Genome research.

[20]  J. Wegiel,et al.  Trisomy-driven overexpression of DYRK1A kinase in the brain of subjects with Down syndrome , 2007, Neuroscience Letters.

[21]  N. Friedman,et al.  Natural history and evolutionary principles of gene duplication in fungi , 2007, Nature.

[22]  Xavier Estivill,et al.  Disorders: Filling the Gaps and Exploring Complexity in Genome-Wide Association Studies , 2022 .

[23]  Timothy B. Stockwell,et al.  The Diploid Genome Sequence of an Individual Human , 2007, PLoS biology.

[24]  Eugene V Koonin,et al.  A common framework for understanding the origin of genetic dominance and evolutionary fates of gene duplications. , 2004, Trends in genetics : TIG.

[25]  Pardis C Sabeti,et al.  Common deletion polymorphisms in the human genome , 2006, Nature Genetics.

[26]  R. Redon,et al.  Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes , 2007, Science.

[27]  E. Birney,et al.  Challenges and standards in integrating surveys of structural variation , 2007, Nature Genetics.

[28]  Stylianos E. Antonarakis,et al.  Chromosome 21 and Down syndrome: from genomics to pathophysiology , 2004, Nature Reviews Genetics.

[29]  S. Otto,et al.  The Evolutionary Consequences of Polyploidy , 2007, Cell.

[30]  Christos A. Ouzounis,et al.  Highly consistent patterns for inherited human diseases at the molecular level , 2006, Bioinform..

[31]  H. Lehrach,et al.  Early vertebrate whole genome duplications were predated by a period of intense genome rearrangement. , 2008, Genome research.

[32]  S. Bottani,et al.  Cellular reactions to gene dosage imbalance: genomic, transcriptomic and proteomic effects. , 2008, Trends in genetics : TIG.

[33]  R. Veitia,et al.  Nonlinear effects in macromolecular assembly and dosage sensitivity. , 2003, Journal of theoretical biology.

[34]  Elizabeth M.C. Fisher,et al.  Down syndrome—recent progress and future prospects , 2009, Human molecular genetics.

[35]  R. Reeves,et al.  Global disruption of the cerebellar transcriptome in a Down syndrome mouse model. , 2003, Human molecular genetics.

[36]  D. Conrad,et al.  Global variation in copy number in the human genome , 2006, Nature.

[37]  B. Tycko,et al.  Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21 , 2006, BMC Medical Genetics.

[38]  R. Veitia,et al.  Exploring the etiology of haploinsufficiency. , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[39]  Karsten Hokamp,et al.  Extensive genomic duplication during early chordate evolution , 2002, Nature Genetics.

[40]  Matthew E Hurles,et al.  The functional impact of structural variation in humans. , 2008, Trends in genetics : TIG.

[41]  M. Delorenzi,et al.  Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance. , 2007, American journal of human genetics.

[42]  Brian C. Thomas,et al.  Gene-balanced duplications, like tetraploidy, provide predictable drive to increase morphological complexity. , 2006, Genome research.

[43]  J. McPherson,et al.  A Chromosome 21 Critical Region Does Not Cause Specific Down Syndrome Phenotypes , 2022 .

[44]  J M Delabar,et al.  Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes. , 2007, American journal of human genetics.

[45]  Richard W. Lusk,et al.  Organismal complexity, protein complexity, and gene duplicability , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Steven Maere,et al.  The gain and loss of genes during 600 million years of vertebrate evolution , 2006, Genome Biology.

[47]  R. Veitia,et al.  Gene Dosage Balance in Cellular Pathways , 2004, Genetics.

[48]  D. Fitzpatrick,et al.  Transcriptional consequences of autosomal trisomy: primary gene dosage with complex downstream effects. , 2005, Trends in genetics : TIG.

[49]  Ingo Ruczinski,et al.  Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart , 2005, Genome Biology.

[50]  Paramvir S. Dehal,et al.  Two Rounds of Whole Genome Duplication in the Ancestral Vertebrate , 2005, PLoS biology.

[51]  R. Guigó,et al.  Global trends of whole-genome duplications revealed by the ciliate Paramecium tetraurelia , 2006, Nature.

[52]  Caleb Webber,et al.  Bias of Selection on Human Copy-Number Variants , 2006, PLoS genetics.

[53]  S. Antonarakis,et al.  Gene duplication: a drive for phenotypic diversity and cause of human disease. , 2007, Annual review of genomics and human genetics.

[54]  Y. Kohara,et al.  Reconstruction of the vertebrate ancestral genome reveals dynamic genome reorganization in early vertebrates. , 2007, Genome research.

[55]  L. Personnaz,et al.  The cerebellar transcriptome during postnatal development of the Ts1Cje mouse, a segmental trisomy model for Down syndrome. , 2005, Human molecular genetics.

[56]  C. Pál,et al.  Dosage sensitivity and the evolution of gene families in yeast , 2003, Nature.

[57]  Xin Gao,et al.  NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21 , 2006, Nature.

[58]  Cathal Seoighe,et al.  Genome duplication led to highly selective expansion of the Arabidopsis thaliana proteome. , 2004, Trends in genetics : TIG.