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Research: Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection
- Jian-Hai Chen,
- Patrick Landback,
- Deanna Arsala,
- Alexander Guzzetta,
- Shengqian Xia,
- Jared Atlas,
- Dylan Sosa,
- Yong E. Zhang,
- Jingqiu Cheng,
- Bairong Shen,
- and Manyuan Long
Genome Res. March 2025 35: 379-392; Published in Advance February 14, 2025, doi:10.1101/gr.279498.124
...million years). Despite this stable pace, we observe distinct patterns in phenotypic enrichment, pleiotropy, and selective pressures across gene ages. Young genes show significant enrichment in diseases related to the male reproductive system, indicating strong sexual selection. Young genes also exhibit...
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Research: Interplay between coding and exonic splicing regulatory sequences
- Nicolas Fontrodona,
- Fabien Aubé,
- Jean-Baptiste Claude,
- Hélène Polvèche,
- Sébastien Lemaire,
- Léon-Charles Tranchevent,
- Laurent Modolo,
- Franck Mortreux,
- Cyril F. Bourgeois,
- and Didier Auboeuf
Genome Res. May 2019 29: 711-722; Published in Advance April 8, 2019, doi:10.1101/gr.241315.118
...selection process relies on RNA binding proteins or splicing factors that enhance or repress exon inclusion following two main principles. First, splicing factors bind to short intronic or exonic motifs (or splicing regulatory sequences) that are often low-complexity sequences composed of the repetition...
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Letter: Complex selection on 5′ splice sites in intron-rich organisms
- Manuel Irimia,
- Scott William Roy,
- Daniel E. Neafsey,
- Josep F. Abril,
- Jordi Garcia-Fernandez,
- and Eugene V. Koonin
Genome Res. November 2009 19: 2021-2027; Published in Advance September 10, 2009, doi:10.1101/gr.089276.108
...boundaries in intron-rich species? Extended complementarity to spliceosomal RNAs can sometimes inhibit splicing (e.g., Staley and Guthrie 1999), and alternatively spliced exons in rodents may be under selection tohaveboundarieswithonlyweakpairing to spliceosomal RNAs (Garg and Green 2007), suggesting...
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Research: Variation in the fitness impact of translationally optimal codons among animals
- Florian Bénitière,
- Tristan Lefébure,
- and Laurent Duret
Genome Res. March 2025 35: 446-458; Published in Advance February 10, 2025, doi:10.1101/gr.279837.124
...that besides TS, synonymous sites can be subject to additional levels of selective constraints. For instance, the presence of splice enhancers located within exons skews codon usage near exon–intron boundaries in mammalian genes (Parmley and Hurst 2007). However, this type of selective pressure is site...
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LETTER: Positive selection acting on splicing motifs reflects compensatory evolution
- Shengdong Ke,
- Xiang H.-F. Zhang,
- and Lawrence A. Chasin
Genome Res. April 2008 18: 533-543; Published in Advance January 18, 2008, doi:10.1101/gr.070268.107
.... Using base substitution rates in intronic regions as a calibrator for neutral change, we found a strong avoidance of synonymous substitutions that disrupt predicted exonic splicing enhancers or create predicted exonic splicing silencers. These results attest to the functionality of the hexameric motif...
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Method: Highly efficient and scarless genome editing via essential gene-coupled homology-directed repair
- Joo Hye Yeo,
- Hyongbum Henry Kim,
- Sang Ho Oh,
- and Jinu Lee
Genome Res. April 15, 2026 gr.281194.125; Published in Advance April 15, 2026, doi:10.1101/gr.281194.125
...disrupt endogenous gene regulation and 106 compromise genomic stability. Thus, selection cassettes are sometimes placed in 107 intronic regions to mitigate this limitation (Wang et al. 2022); however, these can 108 interfere with splicing and generate aberrant transcripts. Meanwhile, “safe harbor” loci...
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Resource: Genetic features and genomic targets of human KRAB-zinc finger proteins
- Jonas de Tribolet-Hardy,
- Christian W. Thorball,
- Romain Forey,
- Evarist Planet,
- Julien Duc,
- Alexandre Coudray,
- Bara Khubieh,
- Sandra Offner,
- Cyril Pulver,
- Jacques Fellay,
- Michael Imbeault,
- Priscilla Turelli,
- and Didier Trono
Genome Res. August 2023 33: 1409-1423; Published in Advance September 20, 2023, doi:10.1101/gr.277722.123
...of selective pressures imposed on its sequence, hence is linked to the relative functional importance of the corresponding protein or protein domain for a given species. Typically, highly constrained coding regions correspond to loci whereas mutations are either associated with disease or are completely absent...
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Resource: Discovery of high-confidence human protein-coding genes and exons by whole-genome PhyloCSF helps elucidate 118 GWAS loci
- Jonathan M. Mudge,
- Irwin Jungreis,
- Toby Hunt,
- Jose Manuel Gonzalez,
- James C. Wright,
- Mike Kay,
- Claire Davidson,
- Stephen Fitzgerald,
- Ruth Seal,
- Susan Tweedie,
- Liang He,
- Robert M. Waterhouse,
- Yue Li,
- Elspeth Bruford,
- Jyoti S. Choudhary,
- Adam Frankish,
- and Manolis Kellis
Genome Res. December 2019 29: 2073-2087; Published in Advance September 19, 2019, doi:10.1101/gr.246462.118
...of these represent new discoveries, including 70 previously undetected protein-coding genes. The novel coding genes are additionally supported by single-nucleotide variant evidence indicative of continued purifying selection in the human lineage, coding-exon splicing evidence from new GENCODE transcripts using next...
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Method: A new approach for rare variation collapsing on functional protein domains implicates specific genic regions in ALS
- Sahar Gelfman,
- Sarah Dugger,
- Cristiane de Araujo Martins Moreno,
- Zhong Ren,
- Charles J. Wolock,
- Neil A. Shneider,
- Hemali Phatnani,
- Elizabeth T. Cirulli,
- Brittany N. Lasseigne,
- Tim Harris,
- Tom Maniatis,
- Guy A. Rouleau,
- Robert H. Brown, Jr,
- Aaron D. Gitler,
- Richard M. Myers,
- Slavé Petrovski,
- Andrew Allen,
- David B. Goldstein,
- and Matthew B. Harms
Genome Res. May 2019 29: 809-818; Published in Advance April 2, 2019, doi:10.1101/gr.243592.118
...-based protein domains as the unit for collapsing, and the other is a gene-level approach that, unlike standard methods, leverages existing evidence of purifying selection against missense variation on said domains. The application of these two collapsing methods to 3093 ALS cases and 8186 controls of European...
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LETTER: Genomic Analysis of the Nuclear Receptor Family: New Insights Into Structure, Regulation, and Evolution From the Rat Genome
- Zhengdong Zhang,
- Paula E. Burch,
- Austin J. Cooney,
- Rainer B. Lanz,
- Fred A. Pereira,
- Jiaqian Wu,
- Richard A. Gibbs,
- George Weinstock,
- and David A. Wheeler
Genome Res. April 2004 14: 580-590; doi:10.1101/gr.2160004
...-binding domain suggests that exon shuffling has played a role in the evolution of this family. An invariant splice junction in all members of the NR family except LXR β suggests a functional role for the intron. The ligand-binding domains of PXR and CAR are among the most divergent in the family. Their higher...

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