Blood XX, Skin XY

Watch

1. A boy whose blood came back female and his skin came back maleyoutube.com/shorts/rYCzxUn_5s0

Word of the day

Parthenogenetic chimaera (par-theh-no-jeh-NET-ik ky-MEER-uh). An individual with two cell lines, one of which developed from an egg without fertilization and carries only maternal chromosomes. Also spelled chimera.

• The Chimera of Arezzo, a bronze statue the Etruscans made about 2,400 years ago, shows the monster as a lion with a goat’s head on its back and a snake for a tail.
• In Spanish, quimera can mean a pipe dream, something impossible to achieve.

Bonus word. Chromosome (from chromo-, “color,” and -some, “body”) names a threadlike body of chromatin carrying genes in a linear order. Wilhelm von Waldeyer-Hartz coined the word in German in the late 1800s for the way chromosomes take up dye.

Predict

1. Masunaga and others, 2021, report a new patient whose body holds a mom-only cell line, made of cells carrying only maternal chromosomes. Before you read the paper by Masunaga and others, make a guess. What percent of their new patient’s white blood cells came from the mom-only line? Write one sentence on why you think so.

   Hint. Think about the boy’s blood in the video. Would every patient follow the same pattern?

Read the paper

Masunaga and others, “Parthenogenetic mosaicism: generation via second polar body retention and unmasking of a likely causative PER2 variant for hypersomnia,” Clinical Epigenetics, 2021. The paper is free to read.

Yohei Masunaga’s team reported a 28-year-old woman with parthenogenetic mosaicism, the paper’s term for a mom-only cell line, and compared her case with five earlier reports. Table 1 of the paper lists all six cases, with the boy from the video as Case 1. For each case, the table gives the other cell lines found (the mom-only line was 46,XX in all six) and the estimated share of mom-only cells in each tissue tested.

1. Quantitative reasoning Table 1 gives the mom-only share in two tissues for five of the six cases, and its last column is blank for your answers. What’s the gap between tissues, in percentage points, for each case in Table 1 with two tissues tested?

   Hint. Subtract the smaller share from the larger one. Keep words like “more than” or “about” in your answer.

2. Quantitative reasoning Genetic tests usually start with blood, and a blood test reads white blood cells. Table 1 gives a white blood cell share for every case except Case 5. For which case in Table 1 would a blood test alone have missed the mom-only line?

   Circle one. Case 1 / Case 2 / Case 3 / Case 4 / Case 6

   Hint. A blood test sees only what the white blood cells carry.

3. Quantitative reasoning In Table 1, five cases have a mom-only share for two different tissues. What do the gaps between tissues in Table 1 tell you about estimating a body-wide share of mom-only cells from one sample?

   Hint. Look at how far apart the two shares are in each case. Would one tissue give the same share as the whole body?

4. Process of science For Case 6, the authors propose that the egg kept its second polar body, which holds sister copies of the egg’s own chromosomes. In Figure 1 and the Results section, regions next to the centromeres carried one version from mom. Some regions farther out carried two different versions from mom. How does crossing over in meiosis I explain the Case 6 pattern of one maternal version near the centromeres and two farther out? And why does that pattern point to one egg instead of two merged embryos?

   Hint. Draw one pair of chromosomes with a crossover partway along. After meiosis I, which parts of the sister copies still match?

5. Information flow The Case 6 patient has idiopathic hypersomnia, a sleep disorder. Exome sequencing found a rare variant in PER2, a circadian clock gene, in 55 of 66 sequencing reads from her and in 25 of 52 reads from her mother, who has no sleep symptoms. What percent of reads carried the PER2 variant in the Case 6 patient, and what percent in the patient’s mother?

   Hint. Divide the variant reads by the total reads for each person.

6. Information flow The PER2 reads from the Case 6 patient come from a mix of mom-only cells and two-parent cells. If 70% of the Case 6 patient’s sequenced cells are mom-only cells with two variant copies of PER2, and each remaining cell has one variant copy, what percent of her PER2 reads would you predict carry the variant?

   Hint. Picture 100 cells. How many variant copies would they hold, out of how many copies in all?

7. Information flow The Case 6 patient’s mother carries one copy of a recessive PER2 variant and has no sleep symptoms. How can a mom-only cell line give a daughter two copies of a recessive variant her mother carries once?

   Hint. Think about how the mom-only line got both copies of each chromosome.

8. Science and society Masunaga and others note a bias in how doctors find people with a mom-only cell line. Genetic tests usually start with blood, and a mom-only line barely present in white blood cells would go unidentified. When should a genetics clinic test a second tissue, such as skin or saliva? And how could testing blood first skew what doctors know about mom-only cell lines? Write your answer as a one-paragraph recommendation to the clinic.

   Hint. Think about which cases a blood test finds first, and which cases never get found.

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