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.

The Molecular Basis of -Thalassemia

“…It is now known that many human diseases (referred to as copy number variants) ranging from color blindness to inherited neuropathies (Carvalho et al 2010) result from unequal exchange of low copy number duplicated sequences in exactly the same way as described in the globin clusters. In these diseases, too, the phenotypes associated with gain or loss of gene product may be quite different.…”

Role ofp53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study

“…73,74 The environmental influence in children with lower SSs is consistent with the higher incidence in AU of damaging mutations in genes linked to epigenetic modification of histones, 73 chromatin remodeling, and cell lineage determination. 75, 76, -Given the antioxidant and prooxidant activities of p53, 77,78 and that genomic instability also has been linked to disorders other than AU, 79 future studies would need to address the role of p53 in nonimmune cells, and more importantly to define the mechanisms by which environmental factors shape this genetic susceptibility resulting in AU.…”

An Evolutionary Biology Approach to Understanding Neurological Disorders

“…It is therefore relevant to explore the origins of human duplicated sequences. Current evidence indicates that many segmental duplications occurred the hominid lineage and, more specifically, in the common ancestor of African great apes (chimpanzee, gorilla, humans) after divergence from the Ponginae or Asian great ape (orangutan) lineage (Bailey & Eichler, 2006;Carvalho et al, 2010;Koszul & Fischer, 2009;Marques-Bonet & Eichler, 2009). A considerable portion of duplicated human sequences have also been found to correspond to expanded gene families, some of which show signatures of positive selection (Marques-Bonet & Eichler, 2009).…”

“…Repeats may also contribute to DNA secondary structures that are more prone to breakage (Yatsenko et al, 2009). One novel aspect of our increased understanding of the role of repetitive DNA sequence in de novo mutations, and our ability to detect such sequences, is that this information can now be used to predict rearrangements that will contribute to genomic disorders (Carvalho et al, 2010;Ou et al, 2011;Sharp et al, 2006). Therefore, while duplicated sequences in primate genomes predispose apes and humans to extensive genetic diversity and biological innovation, the downside is that many de novo genomic changes are mediated by recombination events between these duplications.…”

“…Mutation frequencies also vary widely across the genome, and often concentrate at certain positions or 'hotspots' (see also Sections 3.2, 6.1.2 & 6.2.3), which have structural and functional features affecting mutagenesis (Ananda et al, 2011;Arnheim & Calabrese, 2009;Carvalho et al, 2010;Rogozin & Pavlov, 2003). For example, CpG context elevates the mutation rate by an order of magnitude (Schmidt et al, 2008), non-B DNA structures induced by palindromic AT-rich repeats facilitate recurrent translocations on chromosomes 11 and 22 at positions 11q23 and 22q11 (Kurahashi et al, 2006), while interspersed repetitive elements such as Alu, LINE, long-terminal repeats, and simple tandem repeats are frequently observed at breakpoints in the 9q34.3 subtelomere region (Yatsenko et al, 2009).…”