Gene copy-number polymorphism in nature

Abstract

Differences between individuals in the copy-number of whole genes have been found in every multicellular species examined thus far. Such differences result in unique complements of protein-coding genes in all individuals, and have been shown to underlie adaptive phenotypic differences. Here, we review the evidence for copy-number variants (CNVs), focusing on the methods used to detect them and the molecular mechanisms responsible for generating this type of variation. Although there are multiple technical and computational challenges inherent to these experimental methods, next-generation sequencing technologies are making such experiments accessible in any system with a sequenced genome. We further discuss the connection between copy-number variation within species and copy-number divergence between species, showing that these values are exactly what one would expect from similar comparisons of nucleotide polymorphism and divergence. We conclude by reviewing the growing body of evidence for natural selection on copy-number variants. While it appears that most genic CNVs--especially deletions-are quickly eliminated by selection, there are now multiple studies demonstrating a strong link between copy-number differences at specific genes and phenotypic differences in adaptive traits. We argue that a complete understanding of the molecular basis for adaptive natural selection necessarily includes the study of copy-number variation.

Figure 1.

Detecting duplications and deletions relative to a reference genome using hybridization intensities. (a) When a region of the genome has one copy in the reference genome but two copies in the sample (black rectangles), DNA from both paralogues in the sample hybridize to probes corresponding to the only copy in the reference, resulting in a spike in hybridization intensity at these probes (illustrated by the elevated intensities directly below the copy in the reference). The location of the additional copy present in the sample genome is denoted with an arrow in the reference genome. (b) When a region of the genome has one copy in the reference genome (black rectangle) but no copies in the sample, hybridization intensity is significantly diminished at probes corresponding to the sequence missing from the sample.

Figure 2.

Detecting insertions and deletions using paired-end mapping data. The ends of a DNA fragment from a sample individual are mapped to a reference genome. In both of these illustrations, a depiction of the DNA fragment appears above its location in the sample chromosome. The black and grey ends correspond to the unique sequenced ends of the fragment, and the expected length of the sequence is shown above the sample chromosome. Dashed lines indicate homologous regions in the two genomes, and the location of the black and grey ends below the reference chromosome corresponds to their mapped locations. (a) If the portion of the reference genome spanned by the fragment ends is larger than expected, then the sample genome probably contains a deletion relative to the reference. (b) If the length of the region spanned by the locations of the end sequences in the reference genome is smaller than expected, then an insertion is inferred to be present in the sample genome.

Figure 3.

Distances between recent gene duplicates in the human genome formed after the human–macaque split (from data presented in McGrath et al. 2009).

Figure 4.

Hybridization-based methods will not detect either deletions in the reference or highly similar duplications in the reference. As in figure 1, sample hybridization intensities are shown under the corresponding regions of the reference genome. (a) If a deletion allele is present in the reference genome (the location is shown by the arrow), then an array designed from the reference will not be able to probe this sequence in sample individuals. (b) If a duplication allele is present in the reference genome, arrays designed from the reference will probably not probe these repetitive regions (shown as diagonal black lines). Because of ambiguous sequence mapping, next-generation sequencing methods will also have difficulty detecting variants in these regions.

Figure 5.

Proportion of duplications and deletions residing within exons, introns, intergenic regions or encompassing complete genes (redrawn from Emerson et al. 2008). Black bars, duplications; white bars, deletions.