Single cell enrichment and genetic analysis workflows in forensic genomics
(A) The standard STR-CE bulk genetic analysis of a complex four-person mixture (diploid cells from each of the individual donors are indicated by different circle colors) is shown in which the bulk sample undergoes a co-extraction of DNA from all four contributors. The genetic analysis results obtained from two (of the twenty or more) STR loci tested are shown in the electropherogram (epg). The peaks on the x axis represent the alleles (designated by the number of tandem repeats detected), and their signal heights on the y axis (measured in relative fluorescence units, RFU) indicate their relative proportions in the mixture. Two alleles (of maternal and paternal origin) are contributed by each donor at each STR locus, who will either be heterozygous (two different alleles) or homozygous (two indistinguishable identical-by-state alleles). In this four-person example there are a total of eight alleles per locus contributed by the contributors. However due to overlapping alleles from some of the donors and homozygosity in one of the donors at each locus in this particular mixture, four (locus 1) or five (locus 2) CE-distinguishable alleles are obtained, and fully deconvoluting the mixture into four individual donor genotypes is challenging.
(B) The use of a bulk enrichment process (using MACS, FACS, or DE) prior to the genetic analysis reduces the complexity of the original bulk mixture (into two subpopulations in this instance), but mixture deconvolution, albeit simpler, is still required.
(C) Direct single cell subsampling from the bulk mixture (using the DEPArray digital cell sorting system, laser capture microscopy [LCM] or micromanipulation [MM]) and subsequent genetic analysis of single cells can result in complete deconvolution of the mixture into single source genotype information from each of the donors. It is possible to combine bulk enrichment and single cell genetic analysis (thin arrow) (e.g., sperm and vaginal epithelial cells) but not all cell types and mixtures can be processed in this manner at this time.