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Universit茅 de Strasbourg and partners report that adding structural variants and small insertion鈥揹eletion mutations to single-nucleotide polymorphism analyses raised trait heritability estimates by 14.3% and uncovered broader single gene variant genotype鈥損henotype links in Saccharomyces cerevisiae.

The genome was once considered a sort of blueprint for life, with complete instructions for everything a lifeform needed to become itself. Genetic diversity across populations resists this simple explanation, as differing phenotype traits defy broad genetic variation.

Closer to what has been observed, the genome begins to present as a list of ingredients for life that are assembled distinctly, even when the "blueprint" seems mostly identical.

Past genome-wide trait association work has focused on small variants as the source of differences. But small variants are not enough, as many traits can be influenced by multiple genes at once or a quantitative trait locus (QTL).

In the study, "From genotype to phenotype with 1,086 near telomere-to-telomere yeast genomes," in Nature, researchers assembled genomes and constructed a species-wide structural variant atlas, a gene-based pangenome, and a graph pangenome to dissect how variant classes shape traits.

Long-read sequencing used Oxford Nanopore technology and a hybrid assembly pipeline to generate near telomere-to-telomere genomes from the natural Saccharomyces cerevisiae isolates. Across 1,086 natural isolates, assemblies spanning diverse ecological and geographic origins, built nearly complete, reference-quality genomes for an entire species' natural variation.

Structural variants concentrated in subtelomeric regions and formed 46 hotspots, while single-nucleotide polymorphisms (SNPs) and indels also showed enrichment in these regions with a weaker signal.

Counts reached 6,587 unique structural events from 262,629 redundant calls across isolates, spanning 27.3 Mb (excluding translocations), with classes comprising 4,755 presence鈥揳bsence variations, 1,207 copy-number variations, 231 inversions, and 394 translocations.

Jumping genes, also known as transposons of yeast (Ty) elements, contributed extensively, with Ty sequences covering more than 50% of the length in 39% of presence鈥揳bsence events, 20% of inversions, and 9% of copy-number variations.

Genome-wide associations yielded 7,768 significant links connecting 3,717 traits to 4,564 QTL, including 3,471 SNP-led, 230 indel-led, and 863 structural-variant-led signals. Structural-variant QTL were enriched relative to their genome-wide frequency and showed greater pleiotropy, influencing an average of 2.82 traits compared with 1.45 for SNP-led and 1.34 for indel-led signals.

One hotspot involved a recombination-driven ALD2鈥揂LD3 gene fusion associated with 66 expression traits and 30 growth traits and showed enrichment in Beer and French dairy isolates. Effect-size comparisons placed indel-led QTL highest on average, followed by SNP-led and structural-variant-led signals.

Molecular and organismal phenotypes displayed distinct architectures. Molecular traits carried fewer but stronger-effect associations on average, while growth traits averaged more associations per trait with smaller effects. Structural-variant QTL composed 18.6% of molecular signals and 41.1% of growth signals, indicating a larger contribution to organismal phenotypes within this dataset.

The authors conclude that structural variants, with more traits per locus, contribute disproportionately to complex phenotypes, and that a unified atlas spanning assemblies, a gene-based pangenome, a graph pangenome, and multilayered phenotypes provides groundwork for integrative genome-scale studies in other eukaryotes.

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