Morphometric Analysis of Recognized Genes for Autism Spectrum Disorders and Obesity in Relationship to the Distribution of Protein-Coding Genes on Human Chromosomes

Abstract

Mammalian chromosomes are comprised of complex chromatin architecture with the specific assembly and configuration of each chromosome influencing gene expression and function in yet undefined ways by varying degrees of heterochromatinization that result in Giemsa (G) negative euchromatic (light) bands and G-positive heterochromatic (dark) bands. We carried out morphometric measurements of high-resolution chromosome ideograms for the first time to characterize the total euchromatic and heterochromatic chromosome band length, distribution and localization of 20,145 known protein-coding genes, 790 recognized autism spectrum disorder (ASD) genes and 365 obesity genes. The individual lengths of G-negative euchromatin and G-positive heterochromatin chromosome bands were measured in millimeters and recorded from scaled and stacked digital images of 850-band high-resolution ideograms supplied by the International Society of Chromosome Nomenclature (ISCN) 2013. Our overall measurements followed established banding patterns based on chromosome size. G-negative euchromatic band regions contained 60% of protein-coding genes while the remaining 40% were distributed across the four heterochromatic dark band sub-types. ASD genes were disproportionately overrepresented in the darker heterochromatic sub-bands, while the obesity gene distribution pattern did not significantly differ from protein-coding genes. Our study supports recent trends implicating genes located in heterochromatin regions playing a role in biological processes including neurodevelopment and function, specifically genes associated with ASD.

Keywords: G-negative euchromatin; G-positive heterochromatin; autism spectrum disorder (ASD) genes; chromosome organization; high-resolution chromosome ideograms; obesity genes; protein-coding genes.

Figure 1

Sample chromosome ideogram with protein-coding, autism and obesity gene frequency distributions by Giemsa band. Ideogram representation of chromosome 12 taken from Genome Reference Consortium Ensembl website (http://uswest.ensembl.org/Homo_sapiens/Location/Genome) [21]. PCG = Protein-coding gene distribution, AG = Autism gene distribution, OG = Obesity gene distribution. 1 = Example of color 1 (euchromatin), 2 = Example of color 2 (heterochromatin), 3 = Example of color 3 (heterochromatin), 4 = Example of color 4 (heterochromatin), 5 = Example of color 5 (heterochromatin).

Figure 2

Sample stacked chromosome ideogram.

Figure 3

Giemsa band distributions as a proportion of chromosome length. * = Length of qh, centromeric and/or acrocentric chromosome p arm regions were excluded. Percentage above bar for each chromosome represents the proportion of G-negative euchromatin per chromosome.

Figure 4

Genome-wide distribution of protein-coding, autism and obesity genes by Giemsa band intensity rating. Calculations excluded genes located in the qh, centromeric and acrocentric chromosome p arm regions.

Figure 5

Distribution and proportion of protein-coding, autism and obesity genes by chromosome. * = Length and genes of qh, centromeric and/or acrocentric chromosome p arm regions were excluded. Horizontal black line (—) for each chromosome represents the expected proportion of genes based on chromosome size relative to the total length of all chromosomes summed together.