Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes
Bibliographic record
Abstract
Abstract Humans homozygous or hemizygous for variants predicted to cause a loss of function of the corresponding protein do not necessarily present with overt clinical phenotypes. However, the set of effectively dispensable genes in the human genome has not yet been fully characterized. We report here 190 autosomal genes with 207 predicted loss-of-function variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as loss-of-function, mainly due to linkage disequilibrium with different compensatory variants. Of the 179 remaining variants in 166 genes (0.82% of 20,232 genes), only 11 alleles in 11 genes had previously been confirmed experimentally to be loss-of-function. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes), but depleted of genes expressed in a wide range of organs and in leukocytes. The 125 dispensable non-olfactory receptor genes displayed a relaxation of selective constraints both between species and within humans, consistent with greater redundancy. In total, 62 of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Out of the 179 common loss-of-function variants, 72 could be tested for two neutrality selection statistics, and eight displayed robust signals of positive selection. These variants included the known FUT2 mutant allele conferring resistance to intestinal viruses and an APOL3 variant involved in resistance to parasitic infections. Finally, the 41 dispensable olfactory receptor genes also displayed a strong relaxation of selective constraints similar to that observed for the 341 non-dispensable olfactory receptor genes. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted loss-of-function alleles reveals both redundancies and advantages of such deficiencies for human survival. Significance statement Human genes homozygous for seemingly loss of function (LoF) variants are increasingly reported in a sizeable proportion of individuals without overt clinical phenotypes. Here, we found 166 genes with 179 predicted LoF variants for which the frequency of homozygous individuals exceeds 1% in at least one of the populations present in databases ExAC and gnomAD. This set of putatively dispensable genes showed relaxation of selective constraints suggesting that a large number of these genes are undergoing pseudogenization. Eight of the common LoF variants displayed robust signals of positive selection including two variants located in genes involved in resistance to infectious diseases. The identification of dispensable genes will allow identifying functions that are, at least nowadays, redundant, or possibly advantageous, for human survival.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".