We have found a 2 kilobase insertion containing a rearranged L1 element in the dystrophin gene of a muscular dystrophy patient. We cloned the precursor of this insertion, the second known active human L1 element. The locus, LRE2, has one allele derived from the patient which matches the insertion sequence exactly. LRE2 has a perfect 13-15 bp target site duplication, two open reading frames, and an unusual 21 bp truncation of the 5' end, suggesting that a slightly truncated element can still retrotranspose. It differs from LRE1 by approximately 0.7%. There is an L1 element at LRE2 on approximately 66% of human chromosomes 1q, and the element is absent from chimpanzee and gorilla genomes. These data demonstrate that multiple active L1 elements exist in the human genome, and that a readthrough transcript of an active element is capable of retrotransposition.

Although considered the most common heritable cause of neurodevelopmental disability, precise prevalence figures for the FMR1 mutation in the general population are lacking. Since no fragile X premutation alleles have yet been observed to originate from FMR1 alleles within the normal size range, there is also little information available about the origin of the fragile X premutation and mechanisms leading to instability of the FMR1 trinucleotide repeat region. In this study, 977 genetically unrelated individuals from families unselected for mental retardation or fragile X were analyzed with Southern blot analysis for the presence of FMR1 mutations. A subgroup of subjects with evidence of a large CGG repeat number, and any available relatives, were further studied with PCR to investigate the stability of the trinucleotide repeat segment of FMR1. One subject had a 75 repeat length which was unstable (increased in size) when passed to subsequent generations. This includes one male descendent who had a premutation/full mutation mosaic pattern. Two other alleles with > or = 46 repeats from different subjects were also found to be unstable and increased in size in subsequent generations. Considering all three unstable alleles to be indicative of an evolving or actual premutation, the estimated frequency of the fragile X premutation is one in 510 X chromosomes. However, since 11 other alleles with > or = 46 repeats were found to be stable through at least one meiotic transmission, repeat length appears to be an important but not sufficient condition leading to instability of the FMR1 gene.