A working model for the formation of Robertsonian chromosomes

Abstract

Robertsonian chromosomes form by fusion of two chromosomes that have centromeres located near their ends, known as acrocentric or telocentric chromosomes. This fusion creates a new metacentric chromosome and is a major mechanism of karyotype evolution and speciation. Robertsonian chromosomes are common in nature and were first described in grasshoppers by the zoologist W. R. B. Robertson more than 100 years ago. They have since been observed in many species, including catfish, sheep, butterflies, bats, bovids, rodents and humans, and are the most common chromosomal change in mammals. Robertsonian translocations are particularly rampant in the house mouse, Mus musculus domesticus, where they exhibit meiotic drive and create reproductive isolation. Recent progress has been made in understanding how Robertsonian chromosomes form in the human genome, highlighting some of the fundamental principles of how and why these types of fusion events occur so frequently. Consequences of these fusions include infertility and Down's syndrome. In this Hypothesis, I postulate that the conditions that allow these fusions to form are threefold: (1) sequence homology on non-homologous chromosomes, often in the form of repetitive DNA; (2) recombination initiation during meiosis; and (3) physical proximity of the homologous sequences in three-dimensional space. This Hypothesis highlights the latest progress in understanding human Robertsonian translocations within the context of the broader literature on Robertsonian chromosomes.

Keywords: Chromosomes; Karyotype; Meiosis; Recombination; Robertsonian; Translocation.

Fig. 1.

Karyotypes of Mus musculus domesticus. (A) The laboratory strain of M. m. domesticus has a karyotype of 20 pairs of telocentric chromosomes, in which the centromeres are immediately adjacent to telomeres. Centromeres of all the chromosomes are composed of two types of satellite DNA: minor satellite DNA, where the kinetochore assembles; and major satellite DNA, where the site of sister chromatid cohesion is located. (B) A karyotype is shown from a M. m. domesticus individual from the small volcanic island of Madeira (Britton-Davidian et al., 2000). This karyotype has 11 pairs of metacentric chromosomes that are the result of fusions of the chromosomes indicated. This karyotype is one of six distinct chromosomal ‘races’ documented on Madeira, which are separated from each other by mountain barriers.

Fig. 2.

Human karyotypes. (A) A typical human karyotype with 23 pairs of chromosomes is shown. Chromosomes 13, 14, 15, 21 and 22 are acrocentric, with a short p arm between the centromere (yellow) and the telomere. These chromosomes share regions of striking homology on their p arms, termed PHRs, indicated by the darker color bands. PHRs range in size from 0.7 Mb to 6.5 Mb in the CHM13 genome. Black bands indicate ribosomal DNA arrays. (B) Karyotype depicting a fusion between chromosomes 13 and 14, the most common ROB event in humans. (C) Karyotype depicting a fusion between chromosomes 14 and 21, along with two normal copies of chromosome 21. This karyotype has a normal number of chromosomes but is effectively trisomic for chromosome 21, representing the karyotype of an individual with Down's syndrome.

Fig. 3.

A model for the formation of human Robertsonian chromosomes. (A) Chromosomes 13, 14 and 21, with PHRs shown in darker colors. Centromeres are depicted in yellow. Within each PHR is a macrosatellite DNA array called SST1, which is depicted by an arrowhead. The SST1 array contains predicted binding sites for the meiotic protein PRDM9 and is inverted on chromosome 14. A crossover recombination event between chromosome 14 and either chromosome 13 or chromosome 21 will result in the fusion of the two long chromosome arms and the two short (p) arms. The joined p arms, containing part of each PHR, the ribosomal DNA (rDNA) and distal junction sequences, satellite DNAs, and telomeres, are predicted to be lost because they do not have a centromere. The fusion of the long arms will result in a ROB containing SST1 repeats at the breakpoint, flanked by two centromeres, and no ribosomal DNA. (B) This fusion event is facilitated by 3D proximity of the PHRs, which can occur when rDNA arrays from non-homologous chromosomes share the same nucleolus.