A high resolution map of mammalian X chromosome fragile regions assessed by large-scale comparative genomics

Abstract

Chromosomal evolution involves multiple changes at structural and numerical levels. These changes, which are related to the variation of the gene number and their location, can be tracked by the identification of syntenic blocks (SB). First reports proposed that ~180-280 SB might be shared by mouse and human species. More recently, further studies including additional genomes have identified up to ~1,400 SB during the evolution of eutherian species. A considerable number of studies regarding the X chromosome's structure and evolution have been undertaken because of its extraordinary biological impact on reproductive fitness and speciation. Some have identified evolutionary breakpoint regions and fragile sites at specific locations in the human X chromosome. However, mapping these regions to date has involved using low-to-moderate resolution techniques. Such scenario might be related to underestimating their total number and giving an inaccurate location. The present study included using a combination of bioinformatics methods for identifying, at base-pair level, chromosomal rearrangements occurring during X chromosome evolution in 13 mammalian species. A comparative technique using four different algorithms was used for optimizing the detection of hotspot regions in the human X chromosome. We identified a significant interspecific variation in SB size which was related to genetic information gain regarding the human X chromosome. We found that human hotspot regions were enriched by LINE-1 and Alu transposable elements, which may have led to intraspecific chromosome rearrangement events. New fragile regions located in the human X chromosome have also been postulated. We estimate that the high resolution map of X chromosome fragile sites presented here constitutes useful data concerning future studies on mammalian evolution and human disease.

Functional and Genomic Features of Human Genes Mutated in Neuropsychiatric Disorders

“…We found that nine NPD genes are located inside or adjacent to fragile regions previously reported in the human X chromosome [23], with 28 NPD genes found to be less conserved among primates (<90% identity) and with 5 NPD genes showing a unique gene structure in humans, compared with orthologues.…”

“…Genes that have a unique gene structure in humans, compared with orthologues, were identified. Additionally, NPD genes that are located near or inside fragile regions of human X chromosome were recognized [23]. …”

Fragile sites, chromosomal lesions, tandem repeats, and disease

“…The onset of bioinformatic methods and databases in recent years provides the potential to simultaneously identify many regions prone to fragility, making them strong candidates for further analysis. Prada and Laissue (2014) used bioinformatic methods to identify chromosomal rearrangements of the X chromosome in 13 different mammalian species ( Prada and Laissue, 2014 ). They identified fragile sites previously associated with the human X chromosome (FRAXA, B, C, D, E, and F), and were also able to determine fragile sites that are conserved between mammalian species, implying that these regions could have functional roles.…”

Success stories in genomic medicine from resource-limited countries

“…Furthermore, innovative diagnostic approaches have been proposed for pathologies having overlapping phenotypes and which are caused by various genes [ 43 , 44 ]. The available data regarding the genomes of particular mammalian species has enabled large-scale comparative genomics approaches leading to dissecting loci related to evolution mechanisms and potentially contributing towards human diseases [ 51 ]. Moreover, complex pathologies such as female infertility have also been explored via NGS (Fonseca et al in press).…”