The evolution and population diversity of human-specific segmental duplications

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Segmental duplications contribute to human evolution, adaptation and genomic instability but are often poorly characterized. We investigate the evolution, genetic variation and coding potential of human-specific segmental duplications (HSDs). We identify 218 HSDs based on analysis of 322 deeply sequenced archaic and contemporary hominid genomes. We sequence 550 human and nonhuman primate genomic clones to reconstruct the evolution of the largest, most complex regions with protein-coding potential (N = 80 genes from 33 gene families). We show that HSDs are non-randomly organized, associate preferentially with ancestral ape duplications termed ‘core duplicons’ and evolved primarily in an interspersed inverted orientation. In addition to Homo sapiens-specific gene expansions (such as TCAF1/TCAF2), we highlight ten gene families (for example, ARHGAP11B and SRGAP2C) where copy number never returns to the ancestral state, there is evidence of mRNA splicing and no common gene-disruptive mutations are observed in the general population. Such duplicates are candidates for the evolution of human-specific adaptive traits.

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Figure 1: Identification of HSDs.
Figure 2: Timing of HSDs.
Figure 3: Human CN diversity.
Figure 4: CN polymorphism across diverse populations of TCAF1 and TCAF2 HSDs.
Figure 5: Complex models of HSD evolutionary history.


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We would like to thank many individuals that contributed to the results described here. We thank B. Coe for assistance in statistical analyses, T. Brown for manuscript editing, and L. Vives, T. Wang and B. Xiong for technical assistance with MIP sequencing. We would also like to thank B. Dumont, C. Campbell, K. Meltz Steinberg, S. Girirajan, C. Payan, C. Alkan and E. Karakoc for helpful discussion and advice. We thank M. Kremitzki for technical support in generating sequence maps and contigs of BACs not currently included in the human reference sequence. For DNA samples used in MIP sequencing, we would like to thank the investigators and families participating in the 1KG Project, Autism Speaks, TASC, and SSC. Additionally, we would like to thank the principal investigators involved in the SSC (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren and E. Wijsman). Approved researchers can obtain the SSC population data set described in this study ( by applying at The BAC clones from the complete hydatidiform mole were derived from a cell line created by U. Surti. This work was supported, in part, by US National Institutes of Health (NIH) grants from NINDS (R00NS083627 to M.Y.D.), NIMH (R01MH101221 to E.E.E.) and NHGRI (R01HG002385 to E.E.E., and U41HG007635 to R.K.W. and E.E.E.), as well as The Paul G. Allen Family Foundation (11631 to E.E.E.). S.C. is supported by a National Health and Medical Research Council (NHMRC) CJ Martin Biomedical Fellowship (#1073726). E.E.E. is an investigator of the Howard Hughes Medical Institute.

Author information

M.Y.D. and E.E.E. conceived and designed the experiments. M.Y.D., L.H., B.J.N., O.P., S.C., J.H., F.A., L.D., K.M. and C.E. performed the experiments. M.Y.D., L.H., B.J.N., O.P., S.C. and J.H. analysed data. M.Y.D., K.P., A.R., C.B., M.M., N.J. and K.H. provided technical support. H.A.F.S., X.N., T.A.L.G., R.K.W. and E.E.E. provided materials or analyses tools. M.Y.D., L.H., B.J.N., O.P., S.C. and E.E.E. wrote the paper.

Correspondence to Evan E. Eichler.

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Competing interests

E.E.E. is on the scientific advisory board (SAB) of DNAnexus, Inc., is a consultant for Kunming University of Science and Technology (KUST) as part of the 1000 China Talent Program (2014–2016), and was an SAB member of Pacific Biosciences, Inc. (2009–2013).

Supplementary information

Supplementary Information

Supplementary Figures 1–26; Supplementary Tables 7, 12, 13, 15, 17 and 23; Supplementary Note; Supplementary Discussion; Supplementary Methods; and Supplementary References. (PDF 4818 kb)

Supplementary Tables

Supplementary Tables 1–6, 8–11, 14, 16 and 18–22. (XLSX 1403 kb)

Supplementary Dataset 1

Duplication sequence data including: (1) multiple-sequence alignment (MSA) of HSDs (fastas; labelled 1 through 19 corresponding to labels in Supplementary Dataset 2); (2) visualization of pairwise alignments from MSAs (Align_slider.pdf); and (3) contigs of HSD regions of CH17 BACs not included in reference genome (CH17_contigs.fasta). (ZIP 7776 kb)

Supplementary Dataset 2

Evolutionary analyses of HSDs (XLSX 2749 kb)

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Dennis, M., Harshman, L., Nelson, B. et al. The evolution and population diversity of human-specific segmental duplications. Nat Ecol Evol 1, 0069 (2017) doi:10.1038/s41559-016-0069

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