Beyter D, Ingimundardottir H, Oddsson A, Eggertsson HP, Bjornsson E, Jonsson H, Atlason BA, Kristmundsdottir S, Mehringer S, Hardarson MT, Gudjonsson SA, Magnusdottir DN, Jonasdottir A, Jonasdottir A, Kristjansson RP, Sverrisson ST, Holley G, Palsson G, Stefansson OA, Eyjolfsson G, Olafsson I, Sigurdardottir O, Torfason B, Masson G, Helgason A, Thorsteinsdottir U, Holm H, Gudbjartsson DF, Sulem P, Magnusson OT, Halldorsson BV, Stefansson K.

Nat Genet. 2021 Jun;53(6):779-786. doi:10.1038/s41588-021-00865-4

Long-read sequencing of 3,622 Icelanders provides insight into the role of structural variants in human diseases and other traits.

”We generated [long read sequencing] data from 3,622 Icelanders and identified a median of 22,636 SVs per individual (a median of 13,353 insertions and 9,474 deletions).” “We did not attempt to discover translocations and inversions.“ “We found more SVs, particularly TR SVs, near telomeres, a reflection of the sequence content of telomeres and the high mutation rate of TRs” “The ZnF domain of PRDM9 is the DNA-binding domain, and the SV alleles thus introduce alterations in the DNA-binding motif of PRDM9 and consequently change the locations of meiotic recombination57,58. All the different ZnF-motif lengths showed a strong association with the location of crossovers as measured by the fraction of crossovers that occur in recombination hotspots.”

HELLS and PRDM9 form a pioneer complex to open chromatin at meiotic recombination hot spots.

Spruce C, Dlamini S, Ananda G, Bronkema N, Tian H, Paigen K, Carter GW, Baker CL.

Genes Dev. 2020 Mar 1;34(5-6):398-412. doi:10.1101/gad.333542.119

“[One] chromatin states [...] was enriched for PRDM9-binding sites.” (H3K4me3 > H3K4me1 > H3K36me3 > H3K9ac) “The majority [of the] locations overlap with previously reported locations of B6 meiosis-specific DSBs and PRDM9-dependent H3K4me3 modification.” “Interestingly, compared with other phyla, we did not detect H2A.Z at hot spots in mice.” “At PRDM9-dependent H3K4me3 sites, we detected increased DNA accessibility [ATAC-seq] overlapping with PRDM9 motif locations.” Changing the DNA binding specificity of PRDM9 moved the whole epigenetic mark to new locations. Testis-conditional KO of Hells relocates meiotic DSBs (identified by DMC1 binding) to promoter regions (determined as such by annotation and by chromatin state). The hotspot chromatin state is reduced in Hells mutants, although PRDM9 is still present. “These data show that HELLS is required for establishment of the epigenomic state and chromatin accessibility at hot spots.” Hells interacts with a “PRDM9 variant that lacks the DNA-binding domain (PRDM9ΔZF) [...], suggesting that this interaction is independent of PRDM9-directed DNA binding.” “Critically, upon loss of HELLS, PRDM9C binding at hot spots was reduced to background levels (Fig. 6H). Together, these data show that PRDM9 and HELLS form a complex in vivo and, by extension, suggests that active chromatin remodeling is required for robust PRDM9 binding at hot spots.”