Evolution and diversity of copy number variation in the great ape lineage

Abstract

Copy number variation (CNV) contributes to disease and has restructured the genomes of great apes. The diversity and rate of this process, however, have not been extensively explored among great ape lineages. We analyzed 97 deeply sequenced great ape and human genomes and estimate 16% (469 Mb) of the hominid genome has been affected by recent CNV. We identify a comprehensive set of fixed gene deletions (n = 340) and duplications (n = 405) as well as >13.5 Mb of sequence that has been specifically lost on the human lineage. We compared the diversity and rates of copy number and single nucleotide variation across the hominid phylogeny. We find that CNV diversity partially correlates with single nucleotide diversity (r 2 = 0.5) and recapitulates the phylogeny of apes with few exceptions. Duplications significantly outpace deletions (2.8-fold). The load of segregating duplications remains significantly higher in bonobos, Western chimpanzees, and Sumatran orangutans-populations that have experienced recent genetic bottlenecks (P = 0.0014, 0.02, and 0.0088, respectively). The rate of fixed deletion has been more clocklike with the exception of the chimpanzee lineage, where we observe a twofold increase in the chimpanzee-bonobo ancestor (P = 4.79 3 10 -9 ) and increased deletion load among Western chimpanzees (P = 0.002). The latter includes the first genomic disorder in a chimpanzee with features resembling Smith-Magenis syndrome mediated by a chimpanzee-specific increase in segmental duplication complexity. We hypothesize that demographic effects, such as bottlenecks, have contributed to larger and more gene-rich segments being deleted in the chimpanzee lineage and that this effect, more generally, may account for episodic bursts in CNV during hominid evolution.

Novel H3K4me3 marks are enriched at human- and chimpanzee-specific cytogenetic structures

“…We detected a significant eightfold increase in both the density (P-value = 2 3 10 À21 , permutation P-value = 0.001) and amount of base pairs covered (P-value = 7 3 10 À11 , permutation P-value = 0.001) of human specifically enriched histone modification marks in human-specific segmental duplications (Sudmant et al 2013). Albeit not significant, the segmental duplication-rich 16p11.2-12.2 cytogenetic bands showed a consistent twofold enrichment of these epigenetic marks when compared with the genome average.…”

“…We assessed the possible association between regions with significantly different epigenetic panorama in humans when compared with other primates (Shulha et al 2012) and genomic segments around loci that were structurally modified during the recent evolution of the human genome, i.e., HSA2 fusion point and ancestral centromere, as well as HSA1 and HSA18 inversion breakpoints (Yunis et al 1980;Dennehey et al 2004;Szamalek et al 2006), with HSA1 also encompassing pericentromeric heterochromatin that is absent in its chimpanzee homolog (Yunis et al 1980). Additionally, we assessed highly plastic segments such as human-specific segmental duplications (Sudmant et al 2013) together with subtelomeric and pericentromeric regions (Yunis et al 1980;Bailey et al 2001;Bailey et al 2002;Horvath et al 2003;The Chimpanzee Sequencing and Analysis Consortium 2005;Linardopoulou et al 2005;Locke et al 2005).…”

“…We mapped human, chimpanzee, and macaque reads to the human genome (GRCh37/hg19) using Bowtie (version 0.12.9) (Langmead et al 2009) and called human and chimpanzee peaks using MACS . We filtered peaks with FDR < 0.1, >500 bp, mapped on autosomes, and not overlapping gaps or human/chimpanzee duplications (Sudmant et al 2013). We defined enriched regions 500 bp around the peak summit as suggested in Bardet et al (2012) and merged the humanand chimpanzee-enriched regions.…”

“…Similarly, pericentromeric regions were the first 4 Mbp on either side (p and q chromosomal arms) of the centromere and, when present, the heterochromatin gaps, and the first 4 Mbp on the q-side for acrocentric chromosomes. Coordinates of human-specific and chimpanzee-specific (i.e., present only in human and chimpanzee, respectively) segmental duplications (both fixed duplications and expansions) (Sudmant et al 2013) were converted from the hg18 to the hg19 release using the liftOver tool with default parameters. We retrieved coordinates of HSA1 inversion breakpoints from Szamalek et al (2006); coordinates of HSA18, PTR4 (Pan troglodytes), PTR5, PTR12, PTR16, and PTR17 inversion breakpoints from the UCSC Genome Browser (Chiaromonte et al 2002;Kent et al 2002Kent et al , 2003Schwartz et al 2003); coordinates of PTR9 inversion breakpoint on HSA9q21 from Kehrer-Sawatzki et al (2005c); coordinates of PTR15 inversion breakpoint on HSA15q13 from Locke et al (2003).…”

“…Genome Research 1465 www.genome.org cation data (both fixed duplications and expansions) (Sudmant et al 2013) were converted from the hg18 to the hg19 release using the liftOver tool (-minMatch = 0.5 -minBlocks = 0.5).…”