Cell | 蔺佳栋等绘制近端着丝粒染色体跨代遗传图谱，揭示短臂序列的新生变异及异位重组特征

TL;DR - A Cell paper from Evan Eichler's lab (first author Jiadong Lin) builds the first cross-generational transmission map of human acrocentric chromosome short arms (chr13/14/15/21/22), a long-standing "last unresolved region" of the genome, quantifying their de novo mutation rate and ectopic recombination for the first time. It matters because these regions harbor NORs and drive Robertsonian translocations (carrier frequency ~1/800–1/1000) yet are excluded from nearly all large-scale sequencing studies.

• Method: Combined PacBio HiFi, ONT ultra-long reads, and Hi-C with a new assembly algorithm to haplotype-assemble a 4-generation, 28-member pedigree — 156 short-arm sequences, 64 haplotypes spanning both distal and proximal ends, tracking 107 parent-child transmissions.
• Sequence heterogeneity: Distal and proximal regions share only ~30% and ~70% similarity across acrocentrics; identified chr15-enriched HSat3 variation with distinct methylation, chr13/14/15-specific hypermethylated SST1 satellite, and 12 structural variants in distal junction (DJ) sequences; pseudo-homologous regions (PHRs) confirmed proximally.
• Recombination: Using parents as the reference, ~36.8 Mbp/haplotype of transmitted short-arm sequence yielded 19 recombination events (74% maternal; breakpoints resolved to 0.6 kbp–1.1 Mbp, enriched for PRDM9 motifs). Normal homologous recombination is markedly depleted on the short arms — only one ectopic chr13–chr21 event, driven by a ~600 kbp, 99%-identity segment ~1.6 Mbp from SST1 — while homologous recombination concentrates within 5 Mbp of the centromere on the long arm.
• Mutation spectrum: 103 SNVs and 8 SVs detected; short-arm SNV rate ~1.33×10⁻⁷ per generation (~10× the autosomal average, comparable to the Y chromosome's repetitive regions), with 3× paternal bias and a distinctive spectrum — depleted CpG>TpG but elevated C>G and A>C. Authors propose that high sequence heterogeneity restricts effective synapsis in meiosis I, suppressing normal homologous recombination while degrading DNA repair efficiency, thereby elevating the mutation rate.