Placing human gene families into their evolutionary context

Abstract

Following the draft sequence of the first human genome over 20 years ago, we have achieved unprecedented insights into the rules governing its evolution, often with direct translational relevance to specific diseases. However, staggering sequence complexity has also challenged the development of a more comprehensive understanding of human genome biology. In this context, interspecific genomic studies between humans and other animals have played a critical role in our efforts to decode human gene families. In this review, we focus on how the rapid surge of genome sequencing of both model and non-model organisms now provides a broader comparative framework poised to empower novel discoveries. We begin with a general overview of how comparative approaches are essential for understanding gene family evolution in the human genome, followed by a discussion of analyses of gene expression. We show how homology can provide insights into the genes and gene families associated with immune response, cancer biology, vision, chemosensation, and metabolism, by revealing similarity in processes among distant species. We then explain methodological tools that provide critical advances and show the limitations of common approaches. We conclude with a discussion of how these investigations position us to gain fundamental insights into the evolution of gene families among living organisms in general. We hope that our review catalyzes additional excitement and research on the emerging field of comparative genomics, while aiding the placement of the human genome into its existentially evolutionary context.

Fig. 1

Killer cell Ig-like receptor gene clusters display dramatic gene content variation. A Eleven gene content haplotypes for the human killer cell Ig-like receptor cluster within the leukocyte receptor complex adapted from Middleton and Gonzelez [28]. Framework killer cell Ig-like receptor genes are conserved across haplotypes (gray circles), whereas other genes (color-coded circles) are variably present across haplotypes. Additional haplotypic variation is achieved through a recombination hotspot between KIR3DP1 and KIR2DL4 [29] (small black circle). B Variation in the number and combination of killer cell Ig-like receptor genes within the leukocyte receptor complex in mammalian genomes [–40]. Framework killer cell Ig-like receptor genes are conserved in primates (gray circles) and bounded by conserved flanking genes (black circles). The numbers of killer cell Ig-like receptors with predicted inhibitory (red) and activating (blue) functions vary between species. Additional gene content variation is observed for other gene families within the leukocyte receptor complex (e.g., leukocyte Ig-like receptors and leukocyte-associated Ig-like receptors). The figure is not to drawn scale; it is designed to highlight common sequences (ψ: pseudogene)

Fig. 2

Ly49 and the NKC gene clusters display dramatic gene content variation. A Ly49 haplotypes for four mouse strains adapted from [48] showing genes with sequence homology (color-coded circles) and sets of genes that likely arose through recent duplication events (shaded rectangles). The Ly49 nomenclature as opposed to the standardized Klra# gene nomenclature has been used as some of the genes listed are not in the mouse reference genome and hence do not yet have approved gene symbols. B Gene content variation of Ly49 (KLRA; brown), KLRH (yellow), NKG2/CD94 (KLRC/D; blue), KLRJ (green), KLRI/E (purple), and NKG2D (KLRK; red) genes in the NKC adapted from [293]. The figure is not drawn to scale; it is designed to highlight common sequences (ψ: pseudogene)

Fig. 3

Number of intact chemoreceptors in available tetrapod genomes harvested using methods described in Yohe et al. [147]. Chemoreceptors include olfactory receptor genes (Class I and Class II), vomeronasal receptor (type 1 and type 2) genes, γ-c receptor genes, and trace amine-associated receptors. These counts include genes with > 650-bp open reading frames and do not include any pseudogenes. Silhouettes are from PhyloPic

Fig. 4

Molecular evolution of orchid bee chemosensory receptors. A Males of sibling Euglossa species [335] manufacture perfumes to attract females and differ by a single compound per species (noted as + HNBD/+ L97) in this system [, –338]. B Rates of nonsynonymous substitutions (d_N) in Euglossa chemosensory genes are significantly higher (denoted with asterisk) than in non-chemosensory genes. C d_N versus rates of synonymous substitutions (d_S). Selection analyses reveal candidate chemosensory receptors (e.g., Or41) under divergent selection in the two sister species, potentially related to perfume differences. Figure adapted from Brand et al. [185] under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). If an adaptive hypothesis is maintained, it is expected that the species divergent in OR41 might bind to + L97 in E. viridissima and + HNBD in E. dilemma, but this binding has yet to be experimentally demonstrated

Fig. 5

Vomerolfactory-mediated courtship and territoriality in mouse lemurs and the phylogenetic history of vomeronasal receptor type 1 (V1R) genes in primates. A The urine of the dominant male gray mouse lemur (Microcebus murinus) often contains a distinct steroid-like compound that suppresses reproductive behavior of other males, but it must stand out among competitors to attract females. Dotted-lined arrows indicate a weaker signal among the dominant male urine signal. B Gene tree of V1Rs in primates [187, 191], including the gray mouse lemur. Black branches indicate genes belonging to the mouse lemur, while gray branches belong to other primate groups. C V1R gene tree of lemurs [187], including several species of mouse and dwarf lemurs (Cheirogaleidae). Black branches are Cheirogaleidae and gray branches are other strepsirrhine primates. Sexual selection coupled with extensive gene duplication of vomeronasal receptors may have facilitated rapid speciation in Cheirogaleidae. Silhouettes were obtained from PhyloPic

Fig. 6

Concepts of the phylogenetic informativeness of gene families and the limits of ortholog detection. As lineages diversify (top), the rate of evolution of each lineage impacts the phylogenetic informativeness (PI) of each gene (bottom). In the case of gene families that exhibit relatively slower rates of sequence evolution, phylogenetic information content may continue to accrue over time, thereby increasing the amount of information available for inquiry (blue). In contrast, rapidly evolving loci can exhibit serial substitutions at the same site that erode phylogenetic information (red). The ability to resolve the evolutionary history of such “saturated” loci can be limited