4 ms·

Thanks, that answers my questions about how pedigrees were preprocessed for a study like this: 1. Isn’t there a very high chance any particular male’s result i

Thanks, that answers my questions about how pedigrees were preprocessed for a study like this: 1. Isn’t there a very high chance any particular male’s result is true for both father and uncle? 2. For young teen mothers, sometimes a family of older mother and two assumed siblings is really grandmother, mother, child. Paternity and slightly maternity are secretly, generationally obscured. So two assumed female siblings might share less than half-sibling measures of autosomal DNA.

tetris11 2y ago
It's been a while and I was always a bit shaky on the actual genetics, so hopefully an actual expert can weigh in here, but as far as I remember - For 1 it depends on the penetrance model (a score on whether all individuals with the disease allele(s) express the disease phenotype: 1=all, 0.5=some, etc.) along with whether the allele's mode of inheritance is recessive/dominant, X-linked or not, and how consanguineous/inbred the pedigree is. If I remember it right, if a father/son combo always express the disease allele, then the pedigree is x-linked recessive. If you see an uncle/son combo, and test for it, and the linkage score for the region of interest (the likelihood that the disease travels with the ROI computed over all individuals) goes up, then it's pretty suspect. For 2, you could see the distribution of alleles without much computation. Siblings are expected to share X%, relatives Y%, unrelated Z%. By fitting to these bands, you could already see if the distribution of alleles was suspect. We never tested for mtDNA though, I don't think there were many chipsets for it back then.
- ttyprintk 2y ago
  Awesome, I appreciate that. Ok so my question for the researcher would be: 1. Circumstances where both mtDNA and Y chromosome are shared between biological father and pedigreed father. I think the Biblical term is Levirate marriage. 2. Circumstances without Y where maternity is secretly disputable and paternity uncontentious. I think the researcher called this secret adoption. At distances longer than several generations, is there noise in the measure of autosomal matches such that you cannot detect these?
  - tetris11 2y ago
    I'd argue that after 5 generations your descendants only have (0.5^5) no more than 3% of your genetic material, and if there's some ambiguity to one of your founders (say who has a 50% similarity to the one stated in the pedigree) then that drops to 1% (rounding down). 1% of the human genome (3billion bp) is still 30M bases, which could easily contain 1 or 2 genes which you may have genotyped, depending on the resolution of your genotyping chip (usually 10M markers spread out over the entire genome, and usually clustered around variants/genes of interest). So yeah, even 5 generations down these differences could be detected at the variant level. Even at 10, you could still _theoretically_ find differences. I stress theoretically, because the chance of you having all the individuals from a pedigree genotyped at the same time using the same tech (and thus the same subset of common genotypes to compare) is slim to none. I'd say 5 generations is a rough rule of thumb where the signal is not that much higher than the noise.

tetris11 2y ago

It's been a while and I was always a bit shaky on the actual genetics, so hopefully an actual expert can weigh in here, but as far as I remember - For 1 it depends on the penetrance model (a score on whether all individuals with the disease allele(s) express the disease phenotype: 1=all, 0.5=some, etc.) along with whether the allele's mode of inheritance is recessive/dominant, X-linked or not, and how consanguineous/inbred the pedigree is. If I remember it right, if a father/son combo always express the disease allele, then the pedigree is x-linked recessive. If you see an uncle/son combo, and test for it, and the linkage score for the region of interest (the likelihood that the disease travels with the ROI computed over all individuals) goes up, then it's pretty suspect. For 2, you could see the distribution of alleles without much computation. Siblings are expected to share X%, relatives Y%, unrelated Z%. By fitting to these bands, you could already see if the distribution of alleles was suspect. We never tested for mtDNA though, I don't think there were many chipsets for it back then.

ttyprintk 2y ago
Awesome, I appreciate that. Ok so my question for the researcher would be: 1. Circumstances where both mtDNA and Y chromosome are shared between biological father and pedigreed father. I think the Biblical term is Levirate marriage. 2. Circumstances without Y where maternity is secretly disputable and paternity uncontentious. I think the researcher called this secret adoption. At distances longer than several generations, is there noise in the measure of autosomal matches such that you cannot detect these?
- tetris11 2y ago
  I'd argue that after 5 generations your descendants only have (0.5^5) no more than 3% of your genetic material, and if there's some ambiguity to one of your founders (say who has a 50% similarity to the one stated in the pedigree) then that drops to 1% (rounding down). 1% of the human genome (3billion bp) is still 30M bases, which could easily contain 1 or 2 genes which you may have genotyped, depending on the resolution of your genotyping chip (usually 10M markers spread out over the entire genome, and usually clustered around variants/genes of interest). So yeah, even 5 generations down these differences could be detected at the variant level. Even at 10, you could still _theoretically_ find differences. I stress theoretically, because the chance of you having all the individuals from a pedigree genotyped at the same time using the same tech (and thus the same subset of common genotypes to compare) is slim to none. I'd say 5 generations is a rough rule of thumb where the signal is not that much higher than the noise.