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Intrachromosomal amplification of chromosome 21 (iAMP21) identifies a high-risk subtype of acute lymphoblastic leukaemia (ALL), requiring intensive treatment to reduce their relapse risk. Improved understanding of the genomic landscape of iAMP21-ALL will ascertain whether these patients may benefit from targeted therapy. We performed whole-exome sequencing of eight iAMP21-ALL samples. The mutation rate was dramatically disparate between cases (average 24.9, range 5–51) and a large number of novel variants were identified, including frequent mutation of the RAS/MEK/ERK pathway. Targeted sequencing of a larger cohort revealed that 60% (25/42) of diagnostic iAMP21-ALL samples harboured 42 distinct RAS pathway mutations. High sequencing coverage demonstrated heterogeneity in the form of multiple RAS pathway mutations within the same sample and diverse variant allele frequencies (VAFs) (2–52%), similar to other subtypes of ALL. Constitutive RAS pathway activation was observed in iAMP21 samples that harboured mutations in the predominant clone (⩾35% VAF). Viable iAMP21 cells from primary xenografts showed reduced viability in response to the MEK1/2 inhibitor, selumetinib, in vitro. As clonal (⩾35% VAF) mutations were detected in 26% (11/42) of iAMP21-ALL, this evidence of response to RAS pathway inhibitors may offer the possibility to introduce targeted therapy to improve therapeutic efficacy in these high-risk patients.

Crosses of females from Mormoniella stocks containing pe-333 type cross incompatibility with males from stocks lacking the incompatibility produced progeny that included 29 males with unexpected eye colors. Eight of these males gave rise to stocks that included some individuals with "speckled" eyes, containing sectors or spots of different colors. In these stocks there were unexpectedly low frequencies of transmission of the new phenotypes to progeny. Phenotypes, and results of crosses, are consistent with the hypothesis that the original males and the stocks that they sired contained extra bits of chromatin contributed by the sperm of the males used in the incompatible crosses. In these stocks, these pieces are transmitted with greater frequency by sperm than by eggs, and are occasionally lost in mitosis (producing "speckled" eyes). Data also indicate that the extra chromatin contains only the O and S factors, or the O factor alone, of the eye color locus R. Examination of spermatogonia shows an extra piece of chromatin in cells of males with phenotypes that suggest the presence of such a piece. The piece has not been found in spermatogonia of controls.

Four stocks derived from aberrant segregation of R-locus genes in male progeny following incompatible crosses in Mormoniella have shown characteristics suggesting that genes found on added chromosomal fragments in these stocks have separated from each other. In most cases, this separation was associated with elevated temperatures at the time of and subsequent to fertilization. Data also suggest that the R-locus genes involved are adjacent to a centromere, with the O factor being proximal thereto.