Selfish centromeres and the wastefulness of human reproduction

Abstract

Many human embryos die in utero owing to an excess or deficit of chromosomes, a phenomenon known as aneuploidy; this is largely a consequence of nondisjunction during maternal meiosis I. Asymmetries of this division render it vulnerable to selfish centromeres that promote their own transmission, these being thought to somehow underpin aneuploidy. In this essay, I suggest that these vulnerabilities provide only half the solution to the enigma. In mammals, as in utero and postnatal provisioning is continuous, the costs of early death are mitigated. With such reproductive compensation, selection can favour a centromere because it induces lethal aneuploidy: if, when taken towards the polar body, it instead kills the embryo via aneuploidy, it gains. The model is consistent with the observation that reduced dosage of a murine drive suppressor induces aneuploidy and with the fact that high aneuploidy rates in vertebrates are seen exclusively in mammals. I propose further tests of this idea. The wastefulness of human reproduction may be a price we pay for nurturing our offspring.

Fig 1. The 3 asymmetries of maternal meiosis I.

Here, we consider only 1 of our 23 pairs of chromosomes. Each chromosome, as inherited from the mother or father, is coloured either red or blue. The first step of meiosis I is to replicate each chromosome, generating an X-shaped structure pinched at the centromere (circle at the pinch point of the chromosomes). After meiosis I crossing-over, the chromosome arms swap so causing a change from blue to red of vice versa. The chromosomes in the left figure are seen at this stage. However, with no crossing over at the centromere, segregation during meiosis I always segregates unrelated maternal and paternal centromeres (the relatedness asymmetry). The centromeres attach to spindle microtubules (orange line) that pull the relevant chromosome in 1 of 2 directions. Here, the centromeres and associated kinetochores are shown as 1 entity per chromosome. In reality, there are 2 that tend to co-orient on the same chromosome. One centromere will be dragged to the small polar body, this having no reproductive future (illustrated by a bin), the other to the egg pole, this one then entering meiosis II and having a future. This is the fate asymmetry. The small size of the polar body compared to the egg creates a size asymmetry. The chromosomes align across the meiotic plate (dotted vertical line). Owing to the size asymmetry, this is often located towards where the polar body will appear. This creates a vulnerability in that centromeres can in principle gain information as to which pole they are being dragged, owing to gradients that run across the egg.

Fig 2. Relative rates of meiosis I error in 20,000 human oocytes (data from [53]).

The percentages shown are the percentages of all errors that are each type of error. Missing is class 5, complex errors (21.5%).