Introducing the Y-chromosomal Ancestral-like Reference Sequence-Improving the Capture of Human Evolutionary...

Area of Science:

• Genomics
• Evolutionary Biology
• Bioinformatics

Background:

• Reference sequences are crucial for genetic analysis reproducibility.
• Current human Y chromosome references are evolutionarily young, potentially leading to inaccurate variant calling in evolutionary studies.
• Existing references may not capture the full evolutionary spectrum of the Y chromosome.

Purpose of the Study:

• To construct an ancestral-like human Y chromosome reference sequence.
• To enhance the detection of evolutionarily informative variants on the Y chromosome.
• To provide a tool for annotating Y chromosome variants as ancestral or derived.

Main Methods:

• Applied a weighted maximum parsimony approach to human and primate Y chromosome sequences.
• Constructed an ancestral-like Y chromosome reference sequence.
• Benchmarked the new reference by aligning 40 diverse Y chromosome short-read sequences against it and existing references (GRCh37, GRCh38, T2T-CHM13).
• Developed the 'polaryzer' tool for variant annotation.

Main Results:

• The ancestral-like reference sequence yielded a higher and more consistent number of single nucleotide polymorphisms (SNPs) per sample (mean = 1,400, SD = 77) compared to existing references (mean = 866–968, SD = 457–531).
• Alignments to the ancestral-like reference exclusively called derived SNPs, whereas other references called an average of 46% ancestral SNPs.
• The new reference improved the capture of evolutionary information on the Y chromosome.

Conclusions:

• Existing human Y chromosome reference sequences are suboptimal for capturing evolutionary information.
• The developed ancestral-like Y chromosome reference sequence is a valuable resource for evolutionary applications like TMRCA estimations and phylogenetic analyses.
• The 'polaryzer' tool facilitates the annotation of ancestral and derived variants in Y chromosome data.