Less Is More, Natural Loss-of-Function Mutation Is a Strategy for Adaptation

Abstract

Gene gain and loss are crucial factors that shape the evolutionary success of diverse organisms. In the past two decades, more attention has been paid to the significance of gene gain through gene duplication or de novo genes. However, gene loss through natural loss-of-function (LoF) mutations, which is prevalent in the genomes of diverse organisms, has been largely ignored. With the development of sequencing techniques, many genomes have been sequenced across diverse species and can be used to study the evolutionary patterns of gene loss. In this review, we summarize recent advances in research on various aspects of LoF mutations, including their identification, evolutionary dynamics in natural populations, and functional effects. In particular, we discuss how LoF mutations can provide insights into the minimum gene set (or the essential gene set) of an organism. Furthermore, we emphasize their potential impact on adaptation. At the genome level, although most LoF mutations are neutral or deleterious, at least some of them are under positive selection and may contribute to biodiversity and adaptation. Overall, we highlight the importance of natural LoF mutations as a robust framework for understanding biological questions in general.

Keywords: adaptive evolution; biodiversity; essential genes; loss-of-function; natural variation.

Figure 1

Evolutionary Events Lead to LoF Mutations. (A) Different kinds of LoF mutations. (B) LoF mutations affect different isoforms and the mechanism of the NMD pathway. The LoF mutation only affects a part of the gene transcript in case 1 and affects all transcripts in case 2. Orange rectangles indicate exons, gray rectangles indicate frameshift sequences of exons or retained intron sequences, black lines between them indicate introns, and red lines indicate LoF mutations caused by loss of a start codon or gain of a premature stop codon.

Figure 2

Functional Effects of LoF Mutations. (A) Functional genes without LoF mutation. (B) Gene knockout with LoF mutations. (C) Gene translated into functional protein if LoF mutations are located at 3′ or 5′ termini. (D) Transcriptional readthrough of the premature stop codon. (E) Gene translated to a new functional protein with the LoF mutation. Orange rectangles indicate exons, black lines between them indicate introns, red lines indicate LoF mutations, blue rectangles indicate the core functional domain of the gene, and gray rectangle indicates frameshift. Orange lines with polyadenylic acid indicate mRNA.

Figure 3

The Identification of Essential Genes through LoF Mutations. (A) The identification of single-copy essential genes. The individuals could not survive when LoF mutations occurred in essential genes. (B) The identification of multiple copies of essential genes. When duplication events occurred in essential genes, either one of the copies would be redundant. The individual could survive if LoF mutations occurred in only one of the copies.

Figure 4

Adaptive Evolution of LoF Mutations. LoF mutations can be neutral, deleterious, or advantageous. Deleterious LoF mutations are usually present at low allele frequencies in natural populations due to purifying selection. Neutral or beneficial LoF mutations can be tolerated or may accumulate during range expansion, and beneficial LoF mutations may be fixed by positive selection.