Aldred Patricia M R, Hollox Edward J, Armour John A L
Institute of Genetics, University of Nottingham, Queen's Medical Centre, UK.
Hum Mol Genet. 2005 Jul 15;14(14):2045-52. doi: 10.1093/hmg/ddi209. Epub 2005 Jun 8.
We have defined unexpectedly extensive copy number variation at the human anti-microbial alpha-defensin genes DEFA1 and DEFA3, encoding human neutrophil peptides HNP-1, HNP-2 and HNP-3. There was variation in both number and position of DEFA1/DEFA3 genes in arrays of 19 kb tandem repeats on 8p23.1, so that the DEFA1 and DEFA3 genes appear to be interchangeable variant cassettes within tandem gene arrays. For this reason, the official symbol for this locus has been revised to DEFA1A3. The total number of gene copies per diploid genome varied between four and 11 in a sample of 111 control individuals from the UK, with approximately 10% (11/111) of people lacking DEFA3 completely. DEFA1 appeared to be at high copy number in all great apes studied; at one variable site in the repeat unit, both variants have persisted in humans, chimpanzees and gorillas since their divergence. Analysis of expression levels in human white blood cells showed a clear correlation between the relative proportions of DEFA1:DEFA3 mRNA and corresponding gene numbers. However, there was no relationship between total (DEFA1+DEFA3) mRNA levels and total gene copy number, suggesting the superimposed influence of trans-acting factors. The persistence of DEFA1 at high copy number in other apes suggests an alternative model for the early stages of the evolution of novel genes by duplication and divergence. Duplicated genes present in variant tandem arrays may have greater potential than simple duplications for the combinatorial creation of new functions by recombination and gene conversion, while still preserving pre-existing functions on the same haplotype.
我们发现，人类抗微生物α-防御素基因DEFA1和DEFA3存在意想不到的广泛拷贝数变异，这两个基因编码人类中性粒细胞肽HNP-1、HNP-2和HNP-3。在8p23.1上19kb串联重复序列阵列中，DEFA1/DEFA3基因的数量和位置均存在变异，因此DEFA1和DEFA3基因似乎是串联基因阵列中的可互换变异盒。因此，该基因座的官方符号已修订为DEFA1A3。在来自英国的111名对照个体样本中，每个二倍体基因组的基因拷贝总数在4到11之间变化，约10%（11/111）的人完全缺乏DEFA3。在所有研究的大猿中，DEFA1似乎具有高拷贝数；在重复单元的一个可变位点，自人类、黑猩猩和大猩猩分化以来，两种变异体一直存在。对人类白细胞表达水平的分析表明，DEFA1:DEFA3 mRNA的相对比例与相应基因数量之间存在明显相关性。然而，总（DEFA1+DEFA3）mRNA水平与总基因拷贝数之间没有关系，这表明存在反式作用因子的叠加影响。DEFA1在其他猿类中以高拷贝数持续存在，这为通过复制和分化产生新基因的早期进化阶段提供了另一种模型。存在于变异串联阵列中的重复基因，相比于简单重复，可能具有更大的潜力，通过重组和基因转换组合创造新功能，同时仍在同一单倍型上保留先前存在的功能。
