A global view of human centromere variation and evolution

Area of Science:

• Genetics
• Genomics
• Evolutionary Biology

Background:

• Centromeres are vital for accurate chromosome segregation during cell division.
• Their repetitive sequences have historically made them difficult to study, limiting understanding of centromere diversity.

Purpose of the Study:

• To assemble and characterize centromere diversity across diverse human populations.
• To investigate variations in centromere structure, kinetochore sites, and evolutionary history.

Main Methods:

• Assembled and characterized 2,110 centromeres from diverse individuals using tailored bioinformatic tools.
• Utilized long-read chromatin profiling and multigenerational inheritance studies.
• Compared findings with existing datasets from the Human Pangenome Reference Consortium.

Main Results:

• Identified 226 centromere haplotypes and 1,870 α-satellite variants, revealing extensive centromere diversity.
• Found that ~6% of centromeres have di-kinetochores and <1% have tri-kinetochores, with kinetochore position linked to sequence.
• Observed a 20-fold variation in mutation rates, evidence of archaic hominin introgression, and rapid mutation at kinetochore sites.

Conclusions:

• Centromeres exhibit significant sequence and structural variation, including multiple kinetochore sites.
• Centromere evolution is rapid, driven by an 'arms race' between centromeric sequences and proteins, with evidence of ancient introgression.
• Kinetochore site mutations drive rapid evolution of these essential chromosomal regions.