1. ¹Department of Public Health Sciences, University of Edinburgh, Edinburgh, UK
2. ²Croatian Centre for Global Health, Split, Croatia
3. ³Andrija Stampar School of Public Health, University of Zagreb, Croatia
4. ⁴MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK
5. ⁵Molecular Diagnostic Genotyping Laboratory, Marshfield Clinic Research Foundation, Marshfield, USA

Correspondence: Professor H Campbell, Department of Public Health Sciences, University of Edinburgh, University of Edinburgh Medical School, Teviot Place, Edinburgh EH8 9AG, Scotland. Tel: +44 0 131 650 6984; Fax +44 0 131 650 6909; E-mail: harry.campbell@ed.ac.uk

⁶These authors contributed equally to this work.

Received 15 August 2007; Revised 9 January 2008; Accepted 11 January 2008; Published online 5 March 2008.

Abstract

The human population is undergoing a major transition from a historical metapopulation structure of relatively isolated small communities to an outbred structure. This process is predicted to increase average individual genome-wide heterozygosity (h) and could have effects on health. We attempted to quantify this increase in mean h. We initially sampled 1001 examinees from a metapopulation of nine isolated villages on five Dalmatian islands (Croatia). Village populations had high levels of genetic differentiation, endogamy and consanguinity. We then selected 166 individuals with highly specific personal genetic histories to form six subsamples, which could be ranked a priori by their predicted level of outbreeding. The measure h was then estimated in the 166 examinees by genotyping 1184 STR/indel markers and using two different computation methods. Compared to the value of mean h in the least outbred sample, values of h in the remaining samples increased successively with predicted outbreeding by 0.023, 0.038, 0.058, 0.067 and 0.079 (P<0.0001), where these values are measured on the same scale as the inbreeding coefficient (but opposite sign). We have shown that urbanisation was associated with an average increase in h of up to 0.08–0.10 in this Croatian metapopulation, regardless of the method used. Similar levels of differentiation have been described in many populations. Therefore, changes in the level of heterozygosity across the genome of this magnitude may be common during isolate break-up in humans and could have significant health effects through the established genetic mechanism of hybrid vigour/heterosis.