Biology subjects

Leinonen, J.

Publications and source records attributed to Leinonen, J..

3 recordsLinked to original sources

bioRxiv2025

Introducing the Y chromosome ancestral reference sequence - Improving the capture of human evolutionary information

Reference sequences are essential for reproducible genetic analyses but are often chosen without regard to evolutionary relevance within the analyzed species. The human Y chromosome (chrY) is widely used in evolutionary studies, yet current references represent evolutionarily young sequences, which can lead to misleading variant calling. To address this issue, we constructed a Y-chromosomal ancestral-like reference sequence (Y-ARS) to improve the detection of evolutionarily informative variants on the Y chromosome. The Y-ARS was constructed by applying a weighted maximum parsimony approach to human and primate Y chromosome sequences. To benchmark the performance of the Y-ARS, 40 chrY short-read sequences from diverse haplogroups were aligned to Y-ARS and existing references (GRCh37, GRCh38, and T2T-CHM13). Overall, the Y-ARS yielded the highest and most consistent number of SNPs per sample (mean=1197; SD=105), while other references yielded on average fewer variants (mean=866-968) and showed greater variability across samples (SD=457-531) depending on their phylogenetic distance from the reference. Additionally, alignments to the Y-ARS resulted in calling solely SNPs with evolutionarily derived alleles, while alignments to other references resulted in calling on average 44% SNPs with ancestral alleles. This study demonstrates how the existing reference sequences fail to capture the full range of evolutionary information on the chrY. The Y-ARS improves capturing evolutionary information on the chrY, making it a valuable resource for various evolutionary applications, such as TMRCA estimations and phylogenetic analyses. Finally, alongside the Y-ARS, we provide a publicly available tool, polaryzer, to annotate variants as ancestral or derived in pre-aligned chrY data. Significance statementUsing current reference sequences results in calling genetic variants without information on whether the variant is ancestral or arose later in the species history, which is of interest for evolutionary studies. Here, we tackle this problem for the human Y chromosome by introducing the Y-chromosomal ancestral-like reference sequence, Y-ARS. The Y-ARS overcomes this issue by calling only evolutionarily derived variants on the Y chromosome in a reproducible way, which can directly be used for various downstream analyses in evolutionary genetics.

evolutionary biology↗

bioRxiv2024

Early establishment and life course stability of sex biases in the human brain transcriptome

To elaborate on the origins of the established male-female differences in several brain-related phenotypes, we assessed the patterns of transcriptomic sex biases in the developing and adult human forebrain. We find an abundance of sex differences in expression (sex-DE) in the prenatal brain, driven by both hormonal and sex-chromosomal factors, and considerable consistency in the sex effects between the developing and adult brain, with little sex-DE exclusive to the adult forebrain. Sex-DE was not enriched in genes associated with brain disorder, consistent with systematic differences in the characteristics of these genes (e.g. constraint). Yet, the genes with persistent sex-DE across lifespan were overrepresented in disease gene co-regulation networks, pointing to their potential to mediate sex biases in brain phenotypes. Altogether, our work highlights the prenatal development as a crucial timepoint for the establishment of brain sex differences.

genomics↗

bioRxiv2024

Y chromosome sequencing data suggests dual paths of haplogroup N1a1 into Finland

The paternally inherited Y chromosome is highly informative of genetic ancestry, therefore making it useful in studies of population history. In Finland, two Y- chromosomal haplogroups reveal the major substructure of the population: N1a1 (TAT) enriched in the northeast and I1a (M253) in the southwest, suggested to reflect eastern and western ancestry contributions to the population. Yet, beyond these major Y-chromosomal lineages, the distribution of finer-scale Y- chromosomal variation has not been assessed in Finland. Here we provide the most comprehensive Y-chromosomal study among the Finns up to date, exploiting full sequences for 1,802 geographically mapped Finnish Y chromosomes from the FINRISK project. We assessed the distribution of common Y-chromosomal haplogroups (frequency [≥] 1%) throughout 19 Finnish regions, and further compared the autosomal genetic backgrounds of the Y-chromosomal haplogroups. With such high-resolution data, we identified novel sublineages and geographical enrichment patterns among the major Finnish haplogroups N1a1 (64%), I1a (25%), R1a (4.3%), and R1b (4.8%). Most notably, we discovered that haplogroup N1a1 splits into three major lineages within the country. While two of the sublineages followed a northeastern enrichment pattern observed for N1a1 in general, the sublineage N1a1a1a1a1a (CTS2929) (22% of all samples) displayed an enrichment in the southwest. Further, the carriers of this haplogroup showed a high proportion of southwestern autosomal ancestry unlike the other N1a1 sublineages. Collectively, these results point to distinct demographics within haplogroup N1a1, possibly induced by two distinct arrival routes into Finland. Overall, our study suggests a more complex genetic population history for Finns than previously proposed.

genetics↗