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Review
, 28 (6), 245-57

Exploring the Role of Copy Number Variants in Human Adaptation

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Review

Exploring the Role of Copy Number Variants in Human Adaptation

Rebecca C Iskow et al. Trends Genet.

Abstract

Over the past decade, the ubiquity of copy number variants (CNVs, the gain or loss of genomic material) in the genomes of healthy humans has become apparent. Although some of these variants are associated with disorders, a handful of studies documented an adaptive advantage conferred by CNVs. In this review, we propose that CNVs are substrates for human evolution and adaptation. We discuss the possible mechanisms and evolutionary processes in which CNVs are selected, outline the current challenges in identifying these loci, and highlight that copy number variable regions allow for the creation of novel genes that may diversify the repertoire of such genes in response to rapidly changing environments. We expect that many more adaptive CNVs will be discovered in the coming years, and we believe that these new findings will contribute to our understanding of human-specific phenotypes.

Figures

Figure I
Figure I
Four methods for detecting copy number variants (CNVs). (a) Array comparative genomic hybridization (aCGH) is performed by shearing DNA, often by enzymatic cleavage, heat or sonication. Reference DNA is then labeled with one dye (e.g. Cy3) whereas test DNA is labeled with a different dye (e.g. Cy5). Test and reference DNA are then co-hybridized to an array spotted with thousands of oligonucleotide probes. The relative signal intensities of the dyes for each probe are normalized and then converted to log2 ratios (a positive log2 ratio indicates a gain in the test relative to the reference and a negative log2 ratio indicates a loss). Multiple probes in a region with log2 ratios deviating from 0 are used to make CNV calls. (b) Second-generation sequencing of DNA that has been sheared and ligated to specific adaptors. The resulting sequences are aligned to a reference genome. Read depth across the genome is normalized by GC-content and other parameters and converted to Z-scores. (c) DNA is either cloned into a vector and sequenced by traditional capillary-based methods or sequenced by second-generation technologies as described in (b). Specific algorithms are used when aligning the reads to a reference genome that allow for a gap in the alignment. Such gaps indicate a loss in the test genome relative to the sequenced reference. (d) DNA is size selected and then either cloned into a vector for capillary sequencing or ligated to adaptors and subjected to second-generation sequencing. The ends of the insert are sequenced and aligned to a reference genome. If the ends align further away or closer together than expected based on the distribution of insert sizes, this indicates a loss or a gain in the test genome, respectively.
Figure 1
Figure 1
Schematic depicting positive selection that alters the genomic context of the selected variant and can be detected by tests of neutrality. Lines represent haplotypes in a theoretical population; different colored circles represent single nucleotide polymorphisms (SNPs) on the haplotype; rectangles represent copy number variants (CNVs); and orange shapes represent substrates for positive selection. (a) Theoretical population with representative haplotypes (top). After this population undergoes neutral evolution at this locus for many generations (left), new mutations occur (black circles). The frequencies of some haplotypes and, therefore, some variants, change because of genetic drift. When positive selection occurs (right), the orange variant increases in allelic frequency and reaches fixation (selective sweep). In this example, fixation occurred quickly and recombination has not yet separated the selected variant from other variants on its shared haplotype. Thus, this population exhibits high linkage disequilibrium (LD) at this locus, as indicated by the dashed vertical lines. (b) Theoretical population [as in (a)] with a CNV derived from either a single ancestral event (left) or two independent occurrences in the same region (right). Next, a selective sweep occurs owing to positive selection acting upon the CNV. After the selective pressure has been lifted, the haplotypes are free to accumulate neutral mutations [such as the SNPs (black circles)]. Using measures of LD, extended haplotype homozygosity, population differentiation, Ka/Ks ratios, and the frequency of rare and common variants, this population can be tested for the occurrence of a selective event. Because two different haplotypes were selected for in the scenario on the right, some of these features of selection will be more difficult to ascertain.

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