Biology subjects

Konkel, M. K.

Publications and source records attributed to Konkel, M. K..

3 recordsLinked to original sources

bioRxiv2026

Assembly-independent measurement of human Yq12 heterochromatin reveals population-scale variation and Yq12-derived RNA in testis

Despite advances in long-read sequencing and telomere-to-telomere assembly, population-scale analysis of large satellite arrays remains challenging. Human Yq12 is a megabase-scale heterochromatic region composed primarily of DYZ1/HSat3A6 and DYZ2/HSat1B repeats, whose near-equal proportions are maintained despite extensive variation in total array length. Here, using complete Y-chromosome assemblies, we developed k-mer-based tools to estimate Yq12 size directly from short- and long-read sequencing data without requiring sample-specific complete assemblies. Across 1,597 males from the 1000 Genomes Project, Yq12 length ranged from ~1 to 52 Mb (mean 26.5 Mb) and varied substantially within and between Y haplogroups. Phylogenetic analyses supported long-term constraint of total Yq12 length near an equilibrium of 26 Mb and strongly coupled evolution of DYZ1 and DYZ2 around near-parity composition. In 303 father-son pairs, fathers had longer estimated Yq12 regions in 70.6% of pairs, while sons more often showed DYZ1:DYZ2 ratios closer to 1:1. Testis Iso-Seq identified transcripts containing DYZ1 and DYZ2 satellite sequences, while single-cell RNA-seq revealed their expression in haploid spermatids. These results establish a scalable framework for studying Yq12 population variation, intergenerational dynamics, and transcription, providing new opportunities to investigate how extreme satellite-array variation relates to Y-chromosome evolution and male germ-cell biology.

genetics↗

bioRxiv2025

A global view of human centromere variation and evolution

Centromeres are essential for accurate chromosome segregation during cell division, yet their highly repetitive sequence has historically hindered their complete assembly and characterization. Consequently, the full spectrum of centromere diversity across individuals, populations, and evolutionary contexts remains largely unexplored. Here, we address this gap in knowledge by assembling and characterizing 2,110 complete human centromeres from a diverse cohort of individuals representing 5 continental and 28 population groups. By developing a novel suite of bioinformatic tools tailored for centromeric regions, we uncover previously unknown variation within centromeres, including 226 novel centromere haplotypes and 1,870 new -satellite higher-order repeat (HOR) variants. We find that mobile element insertions are present in 30% of centromeres, with chromosome 16 harboring Alu elements within the kinetochore site at an 11-fold higher frequency than expected. While most centromeres have a single kinetochore site, 6% of them have di-kinetochores, and <<1% have tri-kinetochores, which we confirm with long-read CENP-A CUT&RUN, DiMeLo-seq, and multi-generational inheritance. We further show that the position of the kinetochore is not random and is, instead, closely associated with the underlying sequence and structure of the centromere. To understand the nature of evolutionary change, we compared 2,110 complete human centromeres to 5,747 complete centromeres recently assembled from the Human Pangenome Reference Consortium. We show that centromeres have a >50-fold variation in mutation rate, with the most rapidly mutating centromeres on chromosome 1 and the slowest mutating centromeres on chromosome Y. Additionally, a subset of centromeres show evidence of introgression from archaic hominins, shaping their sequence, structure, and evolutionary history. We validate these centromere mutation rates in a four-generation family, spanning 28 family members and 483 accurately assembled centromeres, and show that the kinetochore site is the most rapidly mutating region in the centromere, with twofold more single-nucleotide variants than the rest of the centromeric -satellite HOR array on average. We propose a model that reveals an arms race between centromeric sequence and proteins, with frequent mutations within the site of the kinetochore that lead to changes in genetic and epigenetic landscapes and, ultimately, rapid evolution of these critically important regions.

genomics↗

bioRxiv2022

Assembly of 43 diverse human Y chromosomes reveals extensive complexity and variation

The prevalence of highly repetitive sequences within the human Y chromosome has led to its incomplete assembly and systematic omission from genomic analyses. Here, we present long-read de novo assemblies of 43 diverse Y chromosomes spanning 180,000 years of human evolution, including two from deep-rooted African Y lineages, and report remarkable complexity and diversity in chromosome size and structure, in contrast with its low level of base substitution variation. The size of the Y chromosome assemblies varies extensively from 45.2 to 84.9 Mbp and include, on average, 81 kbp of novel sequence per Y chromosome. Half of the male-specific euchromatic region is subject to large inversions with a >2-fold higher recurrence rate compared to inversions in the rest of the human genome. Ampliconic sequences associated with these inversions further show differing mutation rates that are sequence context-dependent and some ampliconic genes show evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, the Yq12, is composed of alternating arrays of DYZ1 and DYZ2 repeat units that show extensive variation in the number, size and distribution of these arrays, but retain a 1:1 copy number ratio of the monomer repeats, consistent with the notion that functional or evolutionary forces are acting on this chromosomal region. Finally, our data suggests that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kbp distal to the currently established boundary. The availability of sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of specific traits with Y-chromosomal variants and garnering novel insights into the evolution and function of complex regions of the human genome.

genomics↗