DNA copy number variation is a type of genetic variation in which case the number of copies
of a particular region of a chromosome is altered from its normal state. In the non-repetitive
portion of the human genome, the normal haploid copy number is one – one copy of each
sequence per chromosome. Accordingly, the normal diploid copy number in humans is two –
one copy inherited from both parents. A copy number variant (CNV) can result from either a
loss of copies (most often called a deletion) or gain of copies (called a duplication or
amplification).
In this thesis we studied DNA copy number variation in human – how CNVs emerge and how
they are inherited from parents to offspring. We also analysed CNVs in the context of few
different diseases.
By using DNA microarrays we first aimed to determine if CNVs are associated with mental
retardation (MR). For this we studied not only index cases with MR but larger nuclear families,
where we discovered several already MR-associated CNVs and also a few novel CNV regions
that are possibly associated with predisposition to MR.
Similar study was conducted in couples and females suffering from recurrent miscarriage. By
comparing CNVs and their frequencies in the latter group to these of healthy mothers, we
discovered a multi-copy duplication at 5p13.3 that disrupts PDZD2 and GOLPH3 genes and
significantly increases maternal risk for pregnancy complications.
In the last part of this thesis we studied how CNVs are inherited in Estonian nuclear families
(22 trios and 12 families with multiple siblings) and in HapMap Yoruban trios. We determined
that deletion-carrying chromosomal regions were observed in the offspring slightly less
frequently than expected by random Mendelian inheritance. By analysing duplication-carrying
chromosomal regions in these families, we discovered that in two-thirds of such regions the
duplicated copies of the underlying DNA sequence were not exactly identical but somewhat
different, allowing us to define alternative allelic copies within these copy number gaincarrying chromosomal regions and demonstrating extensive and to-date unmeasured allelic
variability in multi-copy CNV regions of the human genome.