Recurrent chromosomal translocations

Robertsonian translocations (ROBs), resulting from meiotic fusion of two acrocentric chromosomes (13–15, 21, or 22), occur in approximately one in every 1000 newborns. Although most ROB carriers are healthy, they are at increased risk of infertility and spontaneous abortions due to transmission of the unbalanced gametes [22]. ROBs are formed likely due to nonallelic homologous recombination (NAHR) between long stretches of highly similar repetitive satellite DNA sequences in the short arms of acrocentric chromosomes. Numerous examples of various ROB fusion sites have been documented in the literature [23–25].

To date, only a few recurrent non-Robertsonian constitutional translocations have been described in humans. The most frequent t(11;22)(q23;q11.2) results from a rearrangement between palindromic AT-rich repeats (PATRRs) (cruciform structures) [26, 27]. PATRRs were also found to mediate other recurrent constitutional translocations: t(17;22)(q11.2;q11.2) [28], t(4;22)(q35.1;q11.2) [29], t(8;22)(q24.13;q11.21) [30], and t(3;8)(p14.2;q24.1 [31]. In addition, NAHR between inter-chromosomal LCRs (segmental duplications) was shown to result in recurrent constitutional translocations: t(4;8)(p16.2;p23.1), t(4;11)(p16.2;p15.4), and t(8;12)(p23.1;p13.31) [32, 33]. Similarly to ROBs, various recombination sites have been found in the NAHR-mediating LCRs.

Interestingly, breakpoints of the well-known human recurrent pericentric inversion inv(2)(p11.2q13) have been mapped ~ 3 Mb proximal to the HSA2 fusion site [34, 35]. The less frequent fragile site (FRA2B) at 2q13, which has not been fine mapped thus far, may have an impact on the reuse of inv(2)(p11.2q13) and might have influenced the formation of the HSA2 fusion [36].

Homozygosity for constitutional chromosomal aberrations

Very rarely, chromosome aberrations are found in a homozygous state [37, 38]. Thus far, only 13 families with Robertsonian translocation present in a homozygous state (44 chromosomes) have been reported [39–51]. Recently, Song et al. [51] described a healthy 44,XY,der(14;15)(q10;q10),der(14;15)(q10;q10) male with no apparent defects in spermatogenesis and proposed that long term isolation of a group of individuals homozygous for a particular Robertsonian translocation chromosome could theoretically lead to the establishment of a new human subspecies with a full genetic complement in 44 chromosomes. However, to date, no such phenomenon has been reported for modern humans. In contrast to current monogamous social structure, early modern humans are thought to have lived in poly-gamous mating systems, similar to those typical for gorilla [52]. This has likely facilitated HSA2 spreading and its conversion from heterozygous to homozygous state (Fig. 2).

Evolutionary advantage

Out of the HSA2 fusion site directly flanking genes, DDX11L2 expression is restricted to testis, RPL23AP7 and CBWD2 are expressed in the brain, and WASH2P, FAM138B, and RABL2A have expression in the brain and testis higher than in other organs [53, 54]. Transcription profile change of some of these genes in the brain and/or testis might have resulted, respectively, in an improved cognitive functions and/or enhanced fecundity in individuals with heterozygous and homozygous HSA2. Alternatively, given the size of the genomic material absent on HSA2 when compared with Great Apes (Fig. 1), I propose that evolution of these early humans might have been driven primarily by loss of gene(s) in the most subtelomeric regions of the ancestral chromosomes IIp and IIq. Unfortunately, gene content in these genomic regions in Great Apes is currently unknown. Gene loss and pseudogenization have been shown to be pervasive engines of genetic variation during primate speciation [55, 56]. Interestingly, compared to non-human primates, the human genome has had the fewest number of gene losses [57, 58].