The effect of a variant on an organism is always multifaceted and can be considered from multiple perspectives—biochemical, medical, or evolutionary. However, the relationship between the effects of amino acid substitution on protein activity, human health, and an individual’s evolutionary fitness is not trivial. We uncover that the general Lithuanian population is characterized by a “mirror reflection“ of the de novo variant fitness effect, confirming the theory of neutrality. Meanwhile, in the group of individuals with intellectual disability, compared with the reference exome de novo variants significantly changed the composition of the amino acid. Therefore, it predicts that, both in terms of the number of amino acids and changes in their relative fitness, the structure of the proteins encoded by the studied amino acids undergo significant changes following the de novo variant, leading to possible changes in protein function associated with phenotypic traits. These results suggest that the analysis of relative fitness of exome sequences with de novo variants can predict the future phenotype. Therefore even in those cases, then only a few of all functional prediction analysis tools predict a variant as damaging, the negative relative fitness or even adaptability of the genome variant should be carefully evaluated considering both its direct function and the global background of the possible disease-associated mechanism regardless of the phenotype being studied.

变异对生物体的影响总是多方面的，可以从多个角度考虑——生化、医学或进化。然而，氨基酸替代对蛋白质活性、人类健康和个体进化适应性的影响之间的关系并非微不足道。我们发现，一般立陶宛人口的特征是从头变异适应性效应的“镜像” ，证实了中性理论。同时，在智障人群中，与参考外显子组de novo相比变体显着改变了氨基酸的组成。因此，它预测，无论是氨基酸的数量还是它们相对适应性的变化，所研究的氨基酸编码的蛋白质的结构在从头变体后都会发生显着变化，从而导致相关蛋白质功能可能发生变化具有表型特征。这些结果表明，外显子组序列的相对适合度分析与从头变体可以预测未来的表型。因此，即使在这些情况下，所有功能预测分析工具中也只有少数预测变异具有破坏性，考虑到其直接功能和可能疾病的全球背景，应仔细评估基因组变异的负相对适应性甚至适应性-相关机制，与正在研究的表型无关。