Table 1.
Human genes can be grouped into four categories according to their level of redundancy for protective immunity to infection in natural conditions
| Human gene redundancy for host defense | ||||
|---|---|---|---|---|
| Categorya | Low | High | Complete | Beneficial |
| Null allele frequency (MAFb) | Very rare (<10−3) | Rare (<10−2) | Common (>10−2) | Common (>10−2) |
| Clinical penetrancec | Complete | Incomplete | None | High (resistance) |
| Infection spectrum | Broad | Narrow | None | Single (resistance) |
| Natural selection | Negatived | Negative | Neutral | Positive |
| Examples | BTK, RAG1, HAX1 | IL12RB1, IRAK4, CARD9 | TLR5, MBL, CLEC7A | DARC, CCR5, CASP12 |
The four categories are defined for live-born individuals. There is a fifth category of genes, not considered here, for which complete knockouts are embryonic lethal.
MAF values are indicative. For example, a LOF variant with low redundancy can have a MAF >10−3 and a LOF variant with high redundancy may have a MAF > 10−2, especially in a context of incomplete penetrance.
The penetrance is indicative. For example, genes with little redundancy can display incomplete penetrance for some of the associated phenotypes; conversely, genes with high redundancy can show complete penetrance.
Purifying selection might be documented for a few genes with low or even high redundancy, due to purging, although this is more likely to occur for genes that underlie autosomal dominant immunodeficiencies.