Karyomapping: a Universal Method for Genome Wide Analysis of Genetic Disease based on Mapping Crossovers between Parental Haplotypes

Alan H Handyside^1,*, Gary L Harton², Brian Mariani², Alan R Thornhill³, Nabeel A Affara⁴, Marie-Anne Shaw⁵, Darren K Griffin⁶

¹ London Bridge Fertility, Gynaecology and Genetics Centre and University of Leeds, United Kingdom;
² Genetics and IVF Institute, United States;
³ London Bridge Fertility, Gynaecology and Genetics Centre, United States;
⁴ University of Cambridge, United Kingdom;
⁵ University of Leeds, United Kingdom;
⁶ University of Kent, United Kingdom

Correspondence to: Alan H Handyside, London Bridge Fertility, Gynaecology and Genetics Centre, One St Thomas Street, London, SE1 9RY, United Kingdom; ahandyside{at}thebridgecentre.co.uk

Accepted 29 September 2009

The use of genome wide single nucleotide polymorphism (SNP) arrays for high resolution molecular cytogenetic analysis using a combination of quantitative and genotype analysis is well established. Here we demonstrate that by Mendelian analysis of the SNP genotypes of the parents and a sibling or other appropriate family member to establish phase, it is possible to identify informative loci for each of the four parental haplotypes across each chromosome and map the inheritance of these haplotypes and the position of any crossovers in the proband. The resulting ‘karyomap’, unlike a karyotype, identifies the parental and grandparental origin of each chromosome and chromosome segment and is unique for every individual being defined by the independent segregation of parental chromosomes and the pattern of non-recombinant and recombinant chromosomes. Karyomapping, therefore, enables both genome wide linkage based analysis of inheritance and detection of chromosome imbalance where either both haplotypes from one parent are present (trisomy) or neither are present (monsomy/deletion). We also demonstrate that karyomapping is possible at the single cell level following whole genome amplification and, without any prior patient or disease specific test development, provides a universal linkage based methodology for preimplantation genetic diagnosis readily available worldwide.

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