Human Molecular Genetics Advance Access originally published online on June 8, 2005
Human Molecular Genetics 2005 14(14):2045-2052; doi:10.1093/hmg/ddi209
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Copy number polymorphism and expression level variation of the human 
-defensin genes DEFA1 and DEFA3
Institute of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
* To whom correspondence should be addressed. Tel: +44 1159249924; Fax: +44 1159709906; Email: john.armour{at}nottingham.ac.uk
Received March 31, 2005; Revised May 12, 2005; Accepted May 31, 2005
We have defined unexpectedly extensive copy number variation at the human anti-microbial 
-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 
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.
Present Address: Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK.
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