Structural variation, selection, and diversification of the NPIP gene family from the human pangenome

The NPIP gene family is among the most positively selected gene families in humans/apes and drives independent duplication in primate lineages. These duplications promote genetic instability, leading to recurrent disease-associated microduplication and microdeletion syndromes. Despite its importance, little is known about its function or variation in humans, as short-read sequencing cannot distinguish high-identity duplications. Using long-read assemblies of 169 human haplotypes, we find extreme variation in the content and organization of NPIP loci. We identify fixed and polymorphic paralogs and observe ongoing positive selection. With long-read RNA sequencing (RNA-seq), we create paralog-specific gene models, the majority of which were not previously documented, and observe paralog-specific tissue specificity. This analysis of an exceptionally dynamic gene family provides candidates for future functional study.

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Publication Details

Journal
Cell Genomics
Published
2025-08-22
DOI
https://doi.org/10.1016/j.xgen.2025.100977
Citations
5
Primary Topic
Genomic variations and chromosomal abnormalities
Type
article
Field-Weighted Citation Impact
9.09

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article

Structural variation, selection, and diversification of the NPIP gene family from the human pangenome

Evan E. Eichler, Jason G. Underwood, Tomi Pastinen, William T. Harvey et al.
5 citations
Cell Genomics
Genomic variations and chromosomal abnormalities
9.09
article

Structural variation, selection, and diversification of the NPIP gene family from the human pangenome

Evan E. Eichler, Jason G. Underwood, Tomi Pastinen, William T. Harvey, PingHsun Hsieh, Alexandra P. Lewis, Philip C. Dishuck, Max L. Dougherty, Katherine M. Munson
article en
5 citations

Abstract

The NPIP gene family is among the most positively selected gene families in humans/apes and drives independent duplication in primate lineages. These duplications promote genetic instability, leading to recurrent disease-associated microduplication and microdeletion syndromes. Despite its importance, little is known about its function or variation in humans, as short-read sequencing cannot distinguish high-identity duplications. Using long-read assemblies of 169 human haplotypes, we find extreme variation in the content and organization of NPIP loci. We identify fixed and polymorphic paralogs and observe ongoing positive selection. With long-read RNA sequencing (RNA-seq), we create paralog-specific gene models, the majority of which were not previously documented, and observe paralog-specific tissue specificity. This analysis of an exceptionally dynamic gene family provides candidates for future functional study.

Cell GenomicsVol. 5(10)
University of Minnesota (US), Children's Mercy Hospital (US), Howard Hughes Medical Institute (US), University of Washington (US), University of Washington Medical Center (US), Pacific Biosciences (United States) (US), University of Missouri–Kansas City (US)
Howard Hughes Medical Institute, National Institutes of Health
Openalex Percentile: Top 2%
Genomic variations and chromosomal abnormalities
9.09
DOIOpen Access PDFOpenAlex
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