Copy number polymorphism and expression level variation of the human α-defensin genes DEFA1 and DEFA3
Copy number polymorphism and expression level variation of the human α-defensin genes DEFA1 and DEFA3
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DOI：
10.1093/hmg/ddi209
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发表时间：
2005-07-15
影响因子：
3.5
通讯作者：
Armour, JAL
中科院分区：
文献类型：
--
作者：
Aldred, PMR;Hollox, EJ;Armour, JAL
我们在人类抗微生物α -防御素基因DEFA1和DEFA3上发现了出乎意料的广泛拷贝数变异，这些基因编码人类中性粒细胞肽HNP-1、HNP-2和HNP-3。在8p23.1上串联重复序列为19 kb的序列中，DEFA1/DEFA3基因的数目和位置都存在差异，使得DEFA1和DEFA3基因在串联基因序列中表现为可互换的变异磁带。因此，该位点的官方标志已修改为DEFA1A3。在来自英国的111个对照个体的样本中，每个二倍体基因组的基因拷贝总数在4到11之间变化，接近10%（11/111）的人完全缺乏DEFA3。DEFA1基因在所有类人猿中似乎都处于高拷贝数；在重复单元的一个可变位点上，这两种变异自人类、黑猩猩和大猩猩分化以来一直存在。分析人白细胞中DEFA1:DEFA3 mRNA的相对比例与相应的基因数量有明显的相关性。然而，总（DEFA1+DEFA3） mRNA水平与基因总拷贝数之间没有相关性，提示反式作用因素的叠加影响。DEFA1基因在其他类人猿中具有高拷贝数的持久性，这为新基因通过复制和分化进化的早期阶段提供了另一种模式。存在于变异串联阵列中的重复基因可能比简单的重复基因更有潜力通过重组和基因转换来组合创造新的功能，同时在同一单倍型上仍然保留原有的功能。
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 similar to 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.