Biology subjects

Pfennig, A.

Publications and source records attributed to Pfennig, A..

5 recordsLinked to original sources

bioRxiv2026

A Denisovan-derived Alu insertion in OCA2 contributes to pigmentation diversity in present-day Melanesians

Modern humans inherited DNA from Neanderthals and Denisovans, but the contribution of introgressed structural variants (SVs) to present-day human phenotypes and adaptation remains poorly understood. Here, we used a graph-genome approach to genotype 96,277 SVs in 3,332 present-day humans and three high-coverage archaic hominin genomes, identifying 153 candidate introgressed SVs. These SVs are enriched for signatures of local adaptation compared to non-introgressed SVs (p-value = 3.04 x 10-7). Among these, we focused on a Denisovan-derived Alu insertion located in intron 18 of OCA2, a gene central to pigmentation. This introgressed Alu insertion is most frequently observed (> 60%) in Indigenous people from Bougainville Island of Melanesia, and is significantly associated with increased skin pigmentation in this region. To assess its functional impact, the Alu insertion was introduced into human induced pluripotent stem cells (iPSCs), which were subsequently differentiated into melanocytes. Melanocytes harboring the Alu insertion demonstrated elevated OCA2 expression, increased pigmentation, and higher levels of enhancer activity compared to controls. Collectively, these findings highlight introgressed SVs as a significant source of adaptive and phenotypic diversity in modern humans and implicate the Denisovan-derived Alu insertion in OCA2 in pigmentation variation among present-day Melanesian populations.

genomics↗

bioRxiv2026

Harnessing methylation signals inherent in long-read sequencing data for improved variant phasing

Haplotypes are linear sequences of co-inherited alleles along individual chromosomes and are central to genetic mapping, clinical variant interpretation, and inference of population history. However, accurate genome-wide haplotype reconstruction remains challenging. Long-read sequencing has the potential to dramatically improve haplotype inference, but existing methods do not directly leverage all the information embedded in these data. Here, we present LongHap, a read-based phasing method that integrates sequence and 5-methylcytosine (5mC) information in a unified probabilistic framework. By leveraging differentially methylated sites, LongHap resolves phase relationships between variants that are inaccessible to sequence-based approaches alone. Across multiple datasets and sequencing platforms, LongHap increases phase block lengths by up to 30% while substantially reducing switch error rates. LongHap rigorously embeds complex structural variants into the broader haplotype context using loopy belief propagation, enabling improved phasing of INDELs and other variant classes that are inherently difficult to resolve. Methylation-aware phasing also improves the accuracy and contiguity of haplotypes spanning rare variants and structurally complex, medically relevant genes across diverse ancestries, facilitating the interpretation of compound heterozygosity and haplotype-specific regulatory architectures. These results establish methylation-aware phasing as a general framework for improving genome-wide haplotype reconstruction, with broad applications across genetics and genomics.

bioinformatics↗

bioRxiv2024

The evolutionary fate of Neanderthal DNA in 30,780 admixed genomes with recent African-like ancestry

Following introgression, Neanderthal DNA was initially purged from non-African genomes, but the evolutionary fate of remaining introgressed DNA has not been explored yet. To fill this gap, we analyzed 30,780 admixed genomes with African-like ancestry from the All of Us research program, in which Neanderthal alleles encountered novel genetic backgrounds during the last 15 generations. Observed amounts of Neanderthal DNA approximately match expectations based on ancestry proportions, suggesting neutral evolution. Nevertheless, we identified genomic regions that have significantly less or more Neanderthal ancestry than expected and are associated with spermatogenesis, innate immunity, and other biological processes. We also identified three novel introgression desert-like regions in recently admixed genomes, whose genetic features are compatible with hybrid incompatibilities and intrinsic negative selection. Overall, we find that much of the remaining Neanderthal DNA in human genomes is not under strong selection, and complex evolutionary dynamics have shaped introgression landscapes in our species.

evolutionary biology↗

bioRxiv2024

Uncovering the genetic architecture and evolutionary roots of androgenetic alopecia in African men

Androgenetic alopecia is a highly heritable trait. However, much of our understanding about the genetics of male pattern baldness comes from individuals of European descent. Here, we examined a novel dataset comprising 2,136 men from Ghana, Nigeria, Senegal, and South Africa that were genotyped using a custom array. We first tested how genetic predictions of baldness generalize from Europe to Africa, finding that polygenic scores from European GWAS yielded AUC statistics that ranged from 0.513 to 0.546, indicating that genetic predictions of baldness in African populations performed notably worse than in European populations. Subsequently, we conducted the first African GWAS of androgenetic alopecia, focusing on self-reported baldness patterns at age 45. After correcting for present age, population structure, and study site, we identified 266 moderately significant associations, 51 of which were independent (p-value < 10-5, r2 < 0.2). Most baldness associations were autosomal, and the X chromosomes does not appear to have a large impact on baldness in African men. Finally, we examined the evolutionary causes of continental differences in genetic architecture. Although Neanderthal alleles have previously been associated with skin and hair phenotypes, we did not find evidence that European-ascertained baldness hits were enriched for signatures of ancient introgression. Most loci that are associated with androgenetic alopecia are evolving neutrally. However, multiple baldness-associated SNPs near the EDA2R and AR genes have large allele frequency differences between continents. Collectively, our findings illustrate how evolutionary history contributes to the limited portability of genetic predictions across ancestries.

genomics↗

bioRxiv2022

Annotation of Phage Genomes with Multiple Genetic Codes

Some of recently discovered in human gut microbiome highly divergent crAssphages were reported to use multiple genetic codes. Opal or amber stop codon reassignments were present in parts of the genomes, while the standard genetic code was used in the remaining genome sections. Essentially, the phage genomes were divided into distinct blocks where one or another code was used. We have developed a tool, Mgcod, that identifies blocks with specific genetic codes and annotates protein-coding regions. We used Mgcod to scan a large set of human metagenomic contigs. As a result, we identified hundreds of contigs of viral origin with the standard genetic code used in some parts while genetic codes with opal or amber stop codon reassignments were used in others. Many of these contigs originated from known crAssphages. Further investigation revealed that while the genes in one genomic block could be translated by a distinct genetic code, translation of genes by either of the two genetic codes genes in an adjacent block would produce proteins with little difference from each other. The dual-coded genes were enriched with early-stage phage genes, while a single code was used for the late-stage genes. The code-block structure expands the phages ability to infect bacteria whose genomes employ the standard genetic code. The new tool provides means for accurate annotation of unusual genomes of these phages.

bioinformatics↗