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Genetics of mammalian meiosis
Published in C. Yan Cheng, Spermatogenesis, 2018
Meiotic recombination occurs more frequently at certain genomic locations (so-called hotspots) than others.93 The major advance in the study of recombination hotspot is the identification of PRDM9. PRDM9 is a main determinant of meiotic recombination hotspots in mammals.94–96 PRDM9 binds to the 13-mer hotspot consensus DNA motif through its array of DNA-binding zinc fingers. PRDM9 catalyzes both trimethylation of lysine 4 of histone H3 (H3K4me3)97 and trimethylation of lysine 36 of histone H3 (H3K36me3).98 Meiotic recombination hotspots are marked by both H3K4me3 and H3K36me3 modifications.99 H4K44 acetylation (H4K44ac) marks meiotic recombination hotspots in budding yeast but its relationship with mammalian hotspots is unknown.100 PRDM9 directs recombination away from functional genomic elements such as gene promoters.101 The Prdm9 gene is rapidly evolving, especially in the zinc-finger coding region.102 This rapid evolution is driven by the inherent “self-destruct” property of recombination hotspots.95 A recombination hotspot is favored for DSB formation and thus is more likely to be replaced with a coldspot allele through homologous recombination. The 13-mer hotspot consensus motif varies in sequences among species. As a new hotspot consensus emerges, the zinc-finger region of PRMD9 evolves to bind to the new hotspots and vice versa. For example, humanizing the zinc-finger domain of PRDM9 in mice changes the positions of DSB hotspots in mouse.103Prmd9 is the only known mammalian speciation gene and is responsible for the hybrid sterility between mouse subspecies.104 How are H3K4me3-marked hotspots recognized for DSB formation? Recent studies provide insights into the connection of the hotspot to DSB. PRMD9 binding leads to nucleosome depletion at the hotspot, a possible permissive environment for DSB formation.105 PRDM9 interacts with CXXC1, which in turn interacts with IHO1.106 IHO1 is a part of the protein complex that activates SPO11. In addition to CXXC1, PRDM9 interacts with EWSR1, EHMT2, and CDYL.107 In testis, PRDM9 is complexed with REC8, SYCP1, and SYCP3.107 Therefore, the epigenetic and chromatin states specify the location of DSBs and PRDM9 is recruited through association with cohesin and SC.
SPG11: clinical and genetic features of seven Czech patients and literature review
Published in Neurological Research, 2022
Kristyna Doleckova, Jan Roth, Julia Stellmachova, Tomas Gescheidt, Vladimir Sigut, Pavel Houska, Robert Jech, Michael Zech, Martin Vyhnalek, Emilie Vyhnalkova, Pavel Seeman, Anna Uhrova Meszarosova
Two gross intragenic deletions, ex16-18 del and ex37-39 del, were also detected in the Czech SPG11 patients. Gross rearrangements of the SPG11 gene are often the cause of SPG11 and, to date, 23 gross deletions, 3 gross insertions and 4 complex rearrangements are listed in the HGMD Professional database. Conceicao Pereira et al. described that these rearrangements are mediated by the presence of Alu elements (the recombination hotspots) in the SPG11 gene [35]. Therefore careful CNV analysis of HGS data should be performed for the SPG11 patients and MLPA should be performed in patients with only one heterozygous pathogenic variant in the SPG11 gene.
Searching for archaic contribution in Africa
Published in Annals of Human Biology, 2019
Cindy Santander, Francesco Montinaro, Cristian Capelli
In the absence of aDNA from an archaic hominin or ghost population in Africa, we must rely on modern genomes to uncover whether archaic introgression took place. Demographic history alone is not sufficient when using modern genomes as windows into the past. We must also consider biological processes in order to develop tools that aid us in answering questions about our genetic history. Consequently, it is crucial to be aware of the differences in the genomic landscape of different populations. For example, recombination maps have been built for populations with European-ancestry (deCODE, HapMapCEU) (Kong et al. 2010; The HapMap Consortium et al. 2010), West African-ancestry (HapMapYRI) (The HapMap Consortium et al. 2010) and mixed-ancestry (AAmap, AfAdm map) (Hinch et al. 2011; Wegmann et al. 2011). These studies have led to the conclusion that, comparatively, West Africans have more recombination hotspots across the genome than Europeans and, therefore, crossovers are more evenly distributed, leading to shorter LD distances in West Africans (The HapMap Consortium et al. 2010; Hinch et al. 2011). Moreover, these studies have been able to show that recombination events appear to be concentrated at hotspots which correlate with a particular ancestry (The HapMap Consortium et al. 2010; Wegmann et al. 2011). Considering that African populations show the highest levels of genetic diversity in both between- and within-population, it is essential to note that the recombination landscape across Africa may differ and, therefore, LD-based methods developed to search for introgression in non-African populations must be adjusted for these differences. For example, if we wanted to use S* to explore archaic introgression in West Africans, we must account for the shorter extent of LD and, therefore, expect shorter introgressed haplotypes than what is seen in Eurasians, even if admixture putatively took place at a similar date. Mutation rate, too, has been shown to differ between populations and still remains without a final consensus (Narasimhan et al. 2017; Ragsdale et al. 2018).