Evolution in health and medicine Sackler colloquium: Genomic disorders: a window into human gene and genome evolution

Abstract

Gene duplications alter the genetic constitution of organisms and can be a driving force of molecular evolution in humans and the great apes. In this context, the study of genomic disorders has uncovered the essential role played by the genomic architecture, especially low copy repeats (LCRs) or segmental duplications (SDs). In fact, regardless of the mechanism, LCRs can mediate or stimulate rearrangements, inciting genomic instability and generating dynamic and unstable regions prone to rapid molecular evolution. In humans, copy-number variation (CNV) has been implicated in common traits such as neuropathy, hypertension, color blindness, infertility, and behavioral traits including autism and schizophrenia, as well as disease susceptibility to HIV, lupus nephritis, and psoriasis among many other clinical phenotypes. The same mechanisms implicated in the origin of genomic disorders may also play a role in the emergence of segmental duplications and the evolution of new genes by means of genomic and gene duplication and triplication, exon shuffling, exon accretion, and fusion/fission events.

Fig. 1.

Schematic representation of the genome architecture susceptible to rearrangements in the proximal chromosome 17p. The low copy repeats are shown in rectangles (color-coded or similar symbols for given repeats), along with the distribution of the rearrangement breakpoints. (Upper) Diverse alterations (constitutional, evolutionary, somatic) thus far documented for this region. They are color coded for matching the involved segment on 17p. The green horizontal arrow below represents the recurrent duplication and deletion causative of CMT1A and HNPP, respectively; purple horizontal arrows represent the recurrent deletion and duplication causative of SMS and PTLS (3.7 Mb) and the recurrent but uncommon deletion causative of SMS (∼5 Mb). Black arrows below represent the uncommon nonrecurrent deletions and duplications causative of SMS and PTLS, respectively. Solid black line: marker chromosome breakpoints. (Lower) Schematic representation of the isodicentric chromosome 17q, formally designated idic(17)(p11.2), generated according to the model proposed by Barbouti et al. (41) and adapted, with permission, from refs. and .

Fig. 2.

Schematic representation of the MECP2 telomeric region. (Top) Blue boxes represent the pathogenic rearrangements documented in the literature thus far: distal breakpoint grouping of most of the patients with MECP2 duplications, deletions and/or gene conversions of the Opsin genes that cause color blindness, and deletions of the EMD gene that cause Emery–Dreifuss muscular dystrophy (EDMD). (Middle) The genomic context telomeric to MECP2. LCRJ spans 114 kb and is formed by three genes and/or pseudogenes that constitute the Opsin array, OPN1LW, OPN1MW, and TEX28. The nearby LCRs, K1 and K2, are positioned in inverted orientation, have 99% sequence identity, and are 11.3 kb in length. Hatched bars within arrows inside the LCRs K represent the small region that is 100% identical between them. Blue arrows show alignment of the join points of the patients carrying complex rearrangements (triplications embedded in duplications). (Bottom) Human structural variation (yellow rectangles) includes CNVs and inversions; evolutionary genomic rearrangements (orange rectangles) include the duplication of the Opsin gene and further acquisition of the trichromatic color vision during the primate evolution in addition to a recurrent inversion that has been occurring multiple times in eutherians. *, based on data reported in Carvalho et al. (56).

Fig. 3.

Duplication of selected LCRs during molecular evolution of the primates (updated from ref. 122). The figure is not to scale. LCRJ, Opsin and TEX28 array at Xq28; LCR15, LCR highly repeated in chromosome 15q11-q14; LCRK, LCR flanking the genes FLNA and EMD at Xq28; PWS/AS, Prader–Willi and Angelman syndromes; DGS, DiGeorge syndrome; SMS, Smith–Magenis syndrome; WBS, Williams–Beuren syndrome; GBA, glucocerebrosidase gene; NEMO, gene mutated in incontinentia pigmenti; PMCHL1/2, chimeric genes derived from the melanin-concentrating hormone gene; NF1, neurofibromatosis 1; CMT1A, Charcot-Marie-Tooth disease type 1A; LCR16a, low copy repeats on chromosome 16; SMN2, gene mutated in spinal muscular atrophy. This figure was adapted, with permission, from ref. .