A quantitative trait locus for variation in dopamine metabolism mapped in a primate model using reference sequences from related species

Abstract

Non-human primates (NHP) provide crucial research models. Their strong similarities to humans make them particularly valuable for understanding complex behavioral traits and brain structure and function. We report here the genetic mapping of an NHP nervous system biologic trait, the cerebrospinal fluid (CSF) concentration of the dopamine metabolite homovanillic acid (HVA), in an extended inbred vervet monkey (Chlorocebus aethiops sabaeus) pedigree. CSF HVA is an index of CNS dopamine activity, which is hypothesized to contribute substantially to behavioral variations in NHP and humans. For quantitative trait locus (QTL) mapping, we carried out a two-stage procedure. We first scanned the genome using a first-generation genetic map of short tandem repeat markers. Subsequently, using >100 SNPs within the most promising region identified by the genome scan, we mapped a QTL for CSF HVA at a genome-wide level of significance (peak logarithm of odds score >4) to a narrow well delineated interval (<10 Mb). The SNP discovery exploited conserved segments between human and rhesus macaque reference genome sequences. Our findings demonstrate the potential of using existing primate reference genome sequences for designing high-resolution genetic analyses applicable across a wide range of NHP species, including the many for which full genome sequences are not yet available. Leveraging genomic information from sequenced to nonsequenced species should enable the utilization of the full range of NHP diversity in behavior and disease susceptibility to determine the genetic basis of specific biological and behavioral traits.

Fig. 1.

Mapping of the HVA QTL. lod scores for SNP and STR markers in the putative QTL region on vervet 9p are shown. On the horizontal axis is the position of the marker, in megabases, taken from the human physical map, and on the vertical axis is the lod score for the test of the null hypothesis that a QTL is at a given position. SNPs with low observed homozygosity (<75% of vervets homozygous) are indicated with open circles, SNPs with high observed homozygosity (>75% of vervets homozygous) are plotted with crosses, and STRs are plotted with solid squares. In the region between ≈7.5 and ≈17.5 Mb (dashed lines), where the highest lod scores are found, low lod scores were found primarily for uninformative SNPs with high homozygosity. Regions with no significant linkage signal contained both informative and noninformative markers, indicating that the lack of a linkage signal in these regions was not likely because of a lack of informative markers.

Fig. 2.

Vervet and human genome collinearity. The 15-Mb human region (hg18 chr10:5,000,000–20,000,000) encompassing to the area of highest lod scores (orange box) is shown on the University of California, Santa Cruz, browser (http://genome.ucsc.edu). A series of custom tracks displaying vervet BAC end sequence alignments and inferred BAC clone orthologous relationships are also shown. A total of 315 BAC clones displaying appropriate end sequence orientations and distances are presented in green, collectively covering 93% of the interval. A series of BAC clones with noncolinear end sequence alignment results are also shown: four clones (in red) with one end aligning to human chromosome 10 and the other to human chromosome 19 (in red); three clones with both ends aligning to human chromosome 10 on the same DNA strand (in blue); two clones with inferred sizes more than three standard deviations of the average clone size (in green); and two clones (in red) with one end aligning to human chromosome 10 and the other to a different human chromosome. Vervet-mapping STRs are presented in black, and the positions of SNP clusters are shown in red. Known genes are shown in a dense format, highlighting the scarcity of known genes in the D10S1779–D10S585 interval within the area of significant linkage.