Insect Genetics Group
Sex-ratio distorters: genetic elements that bias a population toward males
Most animals produce roughly equal numbers of sons and daughters, but a population's growth depends almost entirely on its females. Only female mosquitoes bite and transmit malaria, and only females lay eggs. If you could tilt the progeny ratio strongly toward males, fewer females would be born each generation, and the population would shrink and eventually collapse. That is the idea behind a sex-ratio distorter (SRD). In many species, the sex of the offspring is decided by the sperm: an X-bearing sperm makes a daughter, a Y-bearing sperm makes a son. So the way to produce mostly sons is to interfere with the X chromosome as sperm are being made.
Premeiotic vs. Postmeiotic: Two ways to bias the ratio
X-shredding: During spermatogenesis, engineered endonucleases recognize and cut the X chromosome across conserved repeats, "shredding" it. Sperm that inherit a shredded X fail to fertilize eggs, so nearly all offspring come from Y-bearing sperm and are sons. This results in prezygotic elimination of the X: the bias is set before fertilization, so the embryos that form are predominantly male.
X-poisoning: Instead of shredding the X, the nuclease targets an haploinsufficient (HI) X-linked gene, meaning one functional copy isn't enough to survive. The sperm still fertilizes the egg, but it delivers a modified X. Sons inherit their father's Y and are unaffected; daughters inherit the modified X, and because their single remaining (maternal) copy can't compensate, they die during development. The bias is therefore postzygotic: the effect appears after fertilization, through the death of daughters rather than the loss of sperm.
Schematic of Y-linked X-shredding and X-poisoning sex ratio distorters. In X-shredding, CRISPR-Cas9 ‘shreds’ a highly repetitive X chromosome-specific sequence in X-bearing sperm, resulting in their absence among successfully fertilizing spermatozoa (prezygotic effect). X-poisoning is based on targeting X-linked haploinsufficient genes HI during spermatogenesis, resulting in dominant lethality of daughters during development (postzygotic effect). Arien et al. 2022
Linking the distorter to the Y chromosome
The Y chromosome is carried only by males and passes strictly from father to son, without recombining with the X. This has two useful consequences: (1) An SRD placed on the Y is inherited by every son, so the element's transmission is coupled to the male bias it produces. (2) Because the Y is never carried by a female, the SRD is shielded from natural selection acting in females. Depending on the design, this makes the system either self-sustaining or self-limiting.
Self-sustaining SRD (Y-linked X-shredder): Because X-shredding acts prezygotically, the Y is passed to more than half of the offspring. That is a meiotic drive: each generation yields more
X-shredder males, which pushes the sex-ratio further toward males and lets the element spread from a small release until the population is suppressed or eliminated. The distortion fuels its own inheritance, which is what makes it self-sustaining. This is the most powerful outcome but the hardest to build: the Y chromosome is largely silenced while sperm are made (likely due to meiotic sex chromosome inactivation), exactly when the X-shredder must act. Overcoming that silencing is a central focus of our lab.
Self-limiting SRD (Y-linked X-poisoner): Alternatively, X-poisoning acts postzygotically: killing daughters after fertilization, so the Y is passed to only half of the offspring. That is not a drive, the element gains no transmission advantage, so it cannot invade and its frequency stays limited on its own. The distortion does not fuel its own inheritance, which is what makes it self-limiting. It is still shielded from selection, since the harm falls only on daughters, who never inherit the Y that caused it. This makes it a contained, reversible option, well suited to situations where a self-spreading system would be undesirable or harder to authorize.
Four sex-ratio distorter designs and how each behaves after a single release of modified males. In postzygotic designs (X-poisoners) daughters die after fertilization; in prezygotic designs (X-shredders) X-bearing sperm are lost before fertilization, so offspring are all sons. Each mechanism can be built on an autosome or on the Y. Only the Y-linked X-shredder is self-sustaining (δ), spreading from a small release because its distortion is coupled to its inheritance. The autosomal designs are self-limiting (α, γ), declining once releases stop, while the Y-linked X-poisoner is effectively neutral (β). shielded from selection in females but with no transmission advantage, so it neither spreads nor is lost.
What we've found
Theory draws a sharp line between X-shredding and X-poisoning; our experiments show that line is easy to cross without realizing it.
In Haber et al. (2024) we set out to build X-poisoners in the malaria mosquito Anopheles gambiae by disrupting X-linked HI genes during spermatogenesis. The strains did produce a male bias, but our analysis showed the bias came mostly from the loss of X-bearing sperm (X-shredding), not from the death of daughters as intended.
In Lamdan et al. (2026) we found the reason. Using a modular ("split") CRISPR-Cas9 system, we varied when the cutting happens during spermatogenesis and which X-linked gene is targeted. The key result: timing, not only the choice of a target gene, decides the outcome. Cutting the X during meiosis led to sperm loss and a male bias, whatever we targeted. Shifting the cutting to earlier stages flipped the mechanism to genuine daughter-killing, most cleanly when targeting the essential muscle gene termed wupA, which killed daughters during development.