Chromosomal variation in neurons of the developing and adult mammalian nervous system

Abstract

A basic assumption about the normal nervous system is that its neurons possess identical genomes. Here we present direct evidence for genomic variability, manifested as chromosomal aneuploidy, among developing and mature neurons. Analysis of mouse embryonic cerebral cortical neuroblasts in situ detected lagging chromosomes during mitosis, suggesting the normal generation of aneuploidy in these somatic cells. Spectral karyotype analysis identified Ϸ33% of neuroblasts as aneuploid. Most cells lacked one chromosome, whereas others showed hyperploidy, monosomy, and͞or trisomy. The prevalence of aneuploidy was reduced by culturing cortical explants in medium containing fibroblast growth factor 2. Interphase fluorescence in situ hybridization on embryonic cortical cells supported the rate of aneuploidy observed by spectral karyotyping and detected aneuploidy in adult neurons. Our results demonstrate that genomes of developing and adult neurons can be different at the level of whole chromosomes.

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

“…Interestingly, age itself is the greatest risk factor for developing AD, and low levels of aneuploidy have also been shown to develop in mature brain neurons because of mitotic defects in neural precursor cells [19,34,51]. The fact that chromosome segregation defects underlie another disease of aging-cancer [4]-suggests that perhaps microtubule disfunction leading to different degrees and types of aneuploidy underlie many manifestations of "normal" aging in addition to predisposing to Alzheimer's disease when chromosome 21 is affected [32].…”

Mammalian nuclear transfer

“…However, because of the inefficiency of nuclear cloning, these experiments do not exclude that DNA rearrangements or loss of genetic material can occur in some cells. For example, DNA rearrangements are frequently found in mature central nervous system neurons (Rehen et al, 2001).…”

Construction of thousands of single cell genome sequencing libraries using combinatorial indexing

“…Estimates of the frequency of aneuploidy and large-scale copy number variation in the mammalian brain have varied widely, spanning a range of <5% to 33% [1][2][3][4] . This uncertainty largely stems from the inability to profile sufficient numbers of single cells to produce quantitative measurements.…”

“…The booming field of single cell sequencing continues to shine light on the abundance and breadth of genomic heterogeneity between cells in a variety of contexts, including somatic gains or losses of megabasepair-sized regions of the genome in the mammalian brain [1][2][3][4] , and tumor heterogeneity and clonal evolution [5][6][7] . Single cell genome sequencing studies have taken one of two approaches: high depth of sequencing per cell for purposes of single nucleotide variant detection 2,8 , or low-pass sequencing to identify copy number variants (CNVs) and the presence of aneuploidy 1,9,10 .…”