Pedigree Tactics ##HOT##
The Israel DNA database has recently started to conduct familial searches (FS). We adopted the CODIS pedigree strategy for FS, which is used in the Unidentified Human Remains (UHR) database and implemented it into the criminal forensic database. This strategy is based on Kinship analysis performed in pedigrees containing DNA profiles from the crime scene designated "unknown," that are then searched against the entire suspects database. A list of candidates is produced and ranked by Joint Pedigree Likelihood Ratio (JPLR). Traditional Y-STR characterizing and mitochondrial sequencing can be performed in order to further minimize the list. Our novel strategy consists of an additional pedigree analysis aimed at prioritizing potential candidates from the candidate list: a Test Pedigree Tree (TPT). Candidates ranked high on the JPLR list can be verified or eliminated from the list by using other close family members included in the database. To further validate this novel strategy, we describe two cases where implementation of this strategy led to a successful match and solved the crime.
Pedigree means different things to decision-makers. In the classic sense, personal pedigree can take into account where you were raised, schools you attended, club memberships, employment history, who you know, and even your race and ancestry. For better or worse, there are many companies that hire employees based largely or exclusively on those external credentials, in order to create a consistent (albeit often elitist) institutional persona.
Take advantage of non-performing, highly credentialed competitors. Some highly credentialed firms will coast on their reputations, and are not as hungry or diligent as their competitors that rely on performance rather than pedigree. This market opportunity often involves mid-sized firms that have engaged high pedigree providers, in hopes of receiving first-class service, only to be disappointed by treatment as second (or third) class citizens.
Once in a while, a Kentucky Derby (G1) contender comes along with a pedigree seemingly perfect for racing 1 1/4 miles on dirt. Such is the case with Rich Strike, the third-place finisher from the Jeff Ruby Steaks (G3).
Efforts to uncover the risk genotypes associated with the familial nature of autism spectrum disorder (ASD) have had limited success. The study of extended pedigrees, incorporating additional ASD-related phenotypes into linkage analysis, offers an alternative approach to the search for inherited ASD susceptibility variants that complements traditional methods used to study the genetics of ASD.
We examined evidence for linkage in 19 extended pedigrees ascertained through ASD cases spread across at least two (and in most cases three) nuclear families. Both compound phenotypes (i.e., ASD and, in non-ASD individuals, the broad autism phenotype) and more narrowly defined components of these phenotypes, e.g., social and repetitive behavior, pragmatic language, and anxiety, were examined. The overarching goal was to maximize the aggregate information available on the maximum number of individuals and to disaggregate syndromic phenotypes in order to examine the genetic underpinnings of more narrowly defined aspects of ASD behavior.
These results provide support for the presence of key features underlying the complexity of the genetic architecture of ASD: substantial between-family locus heterogeneity, that the BAP appears to correspond to sets of subclinical features segregating with ASD within pedigrees, and that different features of the ASD phenotype segregate independently of one another. These findings support the additional study of larger, even more individually informative pedigrees, together with measurement of multiple, behavioral- and biomarker-based phenotypes, in both affected and non-affected individuals, to elucidate the complex genetics of familial ASD.
We recruited extended pedigrees with at least three ASD cases spread across at least two nuclear families (in all but one case, the three cases were spread across three nuclear families). All families were either known to the authors through previous studies or identified through advertising. In all, 19 families were available for this study, 6 recruited in Canada (CA) and 13 in the US. The CA pedigrees had an average of 24 genotyped individuals and 25 phenotyped individuals, while the US pedigrees had an average of 16 genotyped individuals and 18 phenotyped individuals. To minimize etiologic heterogeneity, families were excluded from the study if there was evidence of the following co-occurring medical conditions thought to be etiologically-related to autism in one of the index probands with autism: tuberous sclerosis, neurofibromatosis, phenylketonuria, Fragile X screening, or significant CNS injury. We did not exclude individuals with a chromosome abnormality in order to determine whether that abnormality might also be inherited and play a role in susceptibility. All individuals were of northern European heritage. All data collection took place under Institutional Review Board approval and the research was conducted in accordance with the World Medical Association Declaration of Helsinki . Written informed consent was obtained from all subjects after the study had been fully explained.
Our overarching clinical strategy included clinical assessments performed to i) index eligible extended pedigrees, by identifying at least three related individuals with a Diagnostic and Statistical Manual (4th ed) (DSM-IV) pervasive developmental disorder; and to ii) characterize all pedigree members on phenotypes of interest. For the latter goal of characterizing pedigree members, the strategy employed was to assess for both compound phenotypes (i.e., ASD or, in non-ASD individuals, the BAP) and more narrowly defined components of these phenotypes including social and repetitive behavior, pragmatic language, and anxiety. The overarching goal in taking this multi-tiered approach was to maximize the aggregate information available on the maximum number of affected individuals (i.e., global ratings of ASD or the BAP) as well as to disaggregate these global phenotypes to look at the genetic underpinnings of individual behavioral aspects of the broad construct of autistic behavior.
Four loci show PPL >20% (1p36.32, PPL = 30%; 2q37.2, PPL = 26%; 15q12, PPL = 22%; 22q13.31, PPL = 41%), with additional loci on chromosomes 2, 8, 9, and possibly 12 standing out above the background as well (Figure 1a). Not surprisingly, no single pedigree generates large PPLs on its own. We note however, that on 8q12.1 a modest sequential peak appears to be driven by a single pedigree (PPL = 19% in Ped 4); because the sequential peak is somewhat lower than this, we can conclude that the remaining pedigrees in aggregate show some evidence against linkage to this locus. On 15q11.2, a single pedigree (Ped 16) shows PPL = 15% on its own; however, the sequential peak is >15%, suggesting that while this one pedigree accounts for the preponderance of the evidence, one or more additional pedigrees must also be supporting linkage at this locus. By contrast, PPLs of comparable size on 16q23.1-q23.2 (PPL = 19% in Ped 16) and Xp22.11-p21.3 (PPL = 18% in Ped 5) are almost completely erased in the sequential results. This is consistent with the possibility of major loci within each individual pedigree not found in any of the remaining pedigrees.
Second, ANX, PRS, and SOC show multiple peaks (4 PPLs >20% for ANX, 3 for PRS, 5 for SOC, at a total of 9 loci overall). Apart from 2q37.2-q37.3 (which is best supported by BAP), only 2 loci are strongly supported by 2 or more of these phenotypes (on 9q21.31-22.31, PRS and SOC with slight supporting evidence from ANX; on 13q11-q12.3 ANX and PRS with evidence against linkage for SOC). At the remaining loci, only one phenotype clearly supports linkage; particularly notable in this regard are 9p21.3 and 15q26.3, which are supported by ANX with both PRS and SOC giving evidence against linkage. Thus, in general, there does not seem to be a clear pattern of correlation across these phenotypes. On the contrary, while it is difficult to draw definitive conclusions based on these pedigrees alone, there is some suggestion that the three phenotypes might be picking up different underlying genetic loci. Focusing on the 5 loci with PPL >30% for either ANX, PRS, or SOC (in order to minimize noise due to permutation over the phenotypes): 8q24.13 is supported by SOC with ANX and PRS neutral; 9q21.31-q22.31 is supported by SOC as well as PRS and probably ANX; 13q11-q12.3 is supported by ANX as well as PRS but not SOC; 15q26.3 is supported by ANX but neither PRS or SOC; and 19p12-q12 is supported by SOC but not by ANX, with PRS neutral.
Finally, a striking conclusion emerges regarding RRB. RRB itself gives the two highest PPLs seen for any phenotypes (including in the primary analyses based on all of the pedigrees): PPL = 62% at 6p25.2-24.3, and PPL = 69% at 19p13.3. Each of these loci is at best very slightly supported by one additional phenotype, with the remaining phenotypes either neutral or giving evidence against linkage. Particularly notable is that even ASD and BAP do not support these loci (Figure 5). Furthermore, RRB itself gives evidence against linkage at virtually all of the other loci in Table 3 (with the exceptions of 6p25.3-p25.2 and 12q21.1-q21.33 where it is neutral (note that the maximum PPLs at these 2 loci are
Secondly, in aggregate, our results strongly support the presence of substantial between-pedigree locus heterogeneity for both ASD and BAP analyses. Assuming common loci across pedigrees (PPLPOOL) produced lower PPLs at all loci with PPL >20% compared to allowing for different genetic loci and models across pedigrees (PPLSEQ) (PPLSEQ also returned evidence against linkage across a larger proportion of the genome). Moreover, as previously mentioned, support was found for some previously implicated ASD loci in one individual pedigree but not others. This pattern is consistent with results from the CNV analyses published over the last decade that have shown very little sharing of loci across different families. This highlights the need for locus- and gene-discovery methods that are robust to locus heterogeneity, and should inform our interpretation of negative as well as positive findings going forward. 041b061a72