Complex patterns of male germline instability and somatic mosaicism in myotonic dystrophy type 1

The genetic basis of myotonic dystrophy type 1 (DM1) is the expansion of a CTG repeat in the 3' untranslated region of DM1PK. Once into the disease ra nge, the repeat becomes highly unstable and is biased toward expansion in b oth somatic and germline tissues. Intergenerational differences usually rev eal an increase in allele length, concordant with the clinical anticipation characteristic of DM1, but there have also been cases with intergeneration al contractions of the repeat length, accompanied by apparent anticipation. In order to gain a better understanding of this intergenerational behaviou r, we have obtained semen samples from six DM males and used single molecul e analyses to compare the allele distributions present in their sperm and b lood with those of their offspring. We have confirmed that the male germlin e mutational pathway is distinct from that of the soma, but the extent of v ariation is highly variable from one individual to another and not obviousl y correlated with progenitor allele length. Nonetheless, in all cases the a lleles present in the father's sperm overlap with those observed in their o ffspring. These data also provide further indications that the interpretati on of intergenerational transmissions by standard analyses is frequently co mpromised by the masking of germline differences by age-dependent somatic e xpansion in the parent.