Christine Davis of DavisDNA was perplexed. And with good reason!
A few weeks earlier, she’d uploaded a female client’s AncestryDNA kit to GEDmatch, but GEDmatch flagged the file as male. Assuming the elderly woman had accidentally swapped kits with a male family member, Christine send her a second kit and got the same result.
“Maude” (not her real name) is most definitely female. She is both a mother and grandmother several times over. Aside from normal age-related issues, she is perfectly healthy. And yet GEDmatch had twice insisted she were male.
With Maude’s permission, Christine sent me the “raw data file” containing Maude’s DNA results to see if it contained anything that might explain the GEDmatch error.
Raw Data Files
AncestryDNA raw data files are huge, with more than 650,000 lines of text in five columns: the unique “rsid” for each DNA marker, the chromosome number, the marker position, and then the two states (called alleles) for each marker. Individual alleles can be one of the four DNA bases (A, C, G, or T), or they can be zero when that particular marker is absent in that person.
In the AncestryDNA files, the X chromosome is #23 and the Y chromosome is #24. Chromosomal women normally inherit one copy of the X chromosome from each parent, and their chromosome #23 shows a mix of “heterozygous” positions where the two alleles are different (e.g., AG) and “homozygous” positions where the two alleles are the same (e.g., GG). Chromosomal men normally only have one X chromosome, so their chromosome #23 should appear entirely homozygous in their raw data file.
We also expect differences between men and women on the Y chromosome (#24 in the file). Genetic males should have allele data for chromosome #24 and genetic females will have almost exclusively zeros in their raw data files. That’s because there’s a gene on the Y chromosome called SRY that triggers testes to form during development; in simple terms, SRY is the “boy gene.”
Maude’s DNA Is Atypical
Two things stood out in Maude’s data. First, her X chromosome was entirely homozygous. We expect some homozygous positions on the X, but not all of them.
The image below compares a small portion of my X chromosome with Maude’s. Notice that I have two different base calls at some positions (e.g., the fourth, fifth, and sixth) while Maude has the same base repeated twice for all positions.
That pattern continued for her entire X chromosome. That’s what we’d expect for a man, not a woman.
What’s more, Maude had a string of base calls on the Y chromosome—not the entire Y chromosome, just part. In fact, I didn’t notice it at first; I had to scroll down to find it.
Interestingly, the SRY gene is located around position 2,787,000 on the Y chromosome, while Maude’s Y-DNA bases span positions ≈2,970,000 to ≈6,530,000. That is, it appears that Maude inherited an incomplete Y chromosome without the SRY gene, so she did not develop as a male.
There’s another layer here, though. Women with only one X chromosome have a condition called Turner syndrome; they have characteristic anatomy and are usually infertile. Maude does not have Turner syndrome. She is developmentally normal and birthed several children.
So What Happened?
Truth be told, there are a lot of things that can go off-script in biology, so there are several different explanations for what happened with Maude.
According to Brianne Kirkpatrick, a genetic counselor and genetic genealogist who has worked on unusual and rare cases since 2013, one possibility is called “monosomy rescue.” If so, a normal egg with one X chromosome was fertilized by a sperm with an abnormal Y chromosome. With only one X chromosome and no functional SRY gene, Maude might have been destined to have Turner syndrome. Instead, something else happened. The fertilized egg detected the problem and duplicated the single maternally-inherited X chromosome, producing two identical copies. With two copies of the X and no SRY gene, Maude developed as a typical female.
Biology is full of variation, so this is not the only possible explanation for what happened with Maude. We would need more genetic testing to know for sure. Regardless, Maude is an example of two (or more) rare events that together yielded a healthy, fertile woman.
If the proposed scenario is correct, Maude’s DNA matches should be normal, with the exception that all of her X-chromosome matches will be on her maternal side and none on her paternal side.
Interestingly, if her daughters test, they should be fully identical to one another on the X, because Maude’s two X chromosomes are the same, and their father only has one X to contribute. Similarly, Maude’s sons will match one another and their sisters all the way across the X chromosome.
Many thanks to Christine Davis for sharing this fascinating case and to Brianne Kirkpatrick for stimulating discussion about the possible mechanisms. Finally, credit goes to Nicole Sparks for commenting on the X and Y matching patterns of Maude’s children, which inspired the last section of this post.