Science - USA (2022-02-11)

11 FEBRUARY 2022 • VOL 375 ISSUE 6581 617

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BASED ON MURALIDHAR AND VELLER

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one female-specific—affect expression of

both copies of the gene in an individual.

The regulators’ effects are subject to muta-

tion, causing them to increase or decrease

expression of their associated genes. At the

same time, the genes can accrue mutations,

which are usually deleterious.

A major departure from the classical the-

ory is that, in Lenormand and Roze’s model,

the initial recombination shutdown around

the sex-determining gene does not require

sexual antagonism—only luck. By chance,

some copies of the male-determining gene

will happen to lie on chromosomal tracts

with fewer than average deleterious muta-

tions. A recombination shutdown across

such a tract would “lock in” a high-fitness

stretch of DNA, which would then increase

in frequency. This process can repeat, ex-

panding the region across which recombi-

nation is shut down.

With no genetic exchange between the

proto-X and proto-Y chromosomes, proto-X

and proto-Y cis-regulators can evolve inde-

pendently. Lenormand and Roze identify a

subtle asymmetry in their evolution. Con-

sider a cis-regulator on the proto-X that

has mutated to reduce expression of its

associated gene (also on the proto-X). Be-

cause that copy of the gene is now weakly

expressed, a deleterious mutation in it does

not affect fitness as substantially as if the

gene were strongly expressed, and so it can

sometimes, by chance, spread to apprecia-

ble frequency in the population (together

with the weak cis-regulator). However, as

the mutated gene becomes more common,

it is more often paired with another copy

of itself in females (who carry two proto-X

chromosomes), unmasking its full deleteri-

ous effect. This creates a “frequency-depen-

dent” selection that limits the spread of the

mutated gene and its weak cis-regulator.

Now consider the case of a weak cis-regu-

lator on the proto-Y. Again, because its gene

is weakly expressed, a deleterious mutation

in that gene can, by chance, spread to appre-

ciable frequency. However, because the mu-

tated gene is only ever present in males, its

deleterious effect is always masked by the ho-

mologous gene on the proto-X (which is un-

likely to carry the same mutation). Therefore,

no frequency-dependent selection checks the

spread of the mutated gene (and its weak cis-

regulator). Thus, relative to the proto-X, the

proto-Y tends to evolve weaker cis-regulators,

and this process self-reinforces: Reduced

expression of genes on the proto-Y permits

more deleterious mutations to accumulate,

selecting for even weaker expression to mask

these deleterious mutations ( 12 ).

Reduced expression of the proto-Y would

result in lower-than-optimal sex chromo-

some expression in XY males. This is where

the sex-specific trans-regulators step in:

Male-specific trans-regulators increase

expression of proto-X and proto-Y genes,

returning expression to optimal levels in

males. The result is that, on average across

their two sex chromosomes, males have

weaker cis-regulation and stronger trans-

regulation than females. This sex differ-

ence in balancing cis- and trans-regulation

“locks in” the recombination shutdown on

the proto-Y—if recombination were again

permitted, strong cis-regulators would re-

combine from the proto-X onto the proto-

Y and, in concert with strong male-specific

trans-regulators, push sex chromosome ex-

pression in males above its optimum.

Of these two theories for sex chromo-

some evolution, which is correct? Compli-

cating this question is the substantial scope

for overlap between the theories. For ex-

ample, it is not crucial for the later steps of

Lenormand and Roze’s model whether the

initial recombination shutdown is due to

chance or to sexual antagonism (as in the

classical theory). Similarly, although their

theory does not need selective interference

to explain the accumulation of deleterious

mutations on the proto-Y, this accumula-

tion is accelerated by interference ( 12 ).

Historically, most of our knowledge of

sex chromosome evolution has been built

on ancient systems like the mammalian X

and Y. However, the chronology of events

in the early evolution of these sex chromo-

somes has been substantially obscured by

time, making it difficult to use them to em-

pirically distinguish theories of sex chro-

mosome evolution ( 3 , 4 ). Encouragingly,

attention has recently shifted to young sex

chromosome systems, where genetic sex

determination has newly evolved (as in

many plants) or where the chromosome

that determines sex has switched (as in

several clades of frogs and fish) ( 8 ). These

systems enable direct observation of the

early steps of sex chromosome evolution,

creating opportunities to use experimental

methods to test the causal role of sexual

antagonism in recombination shutdown

( 9 ) and to use molecular and compara-

tive techniques to track the early progres-

sion of dosage compensation ( 10 , 11 ). The

coming years will be exciting for sex chro-

mosome biology, as the full theoretical im-

plications of Lenormand and Roze’s model

are fleshed out and empirical methods that

have been developed for young sex chro-

mosome systems are brought to bear on

the theory. j

REFERENCES AND NOTES

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3. A. E. Wright, R. Dean, F. Zimmer, J. E. Mank, Nat.
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4. D. Charlesworth, Philos. Trans. R. Soc. London Ser. B 372 ,
   20160456 (2017).


5. T. Lenormand, D. Roze, Science 375 , 663 (2022).


6. R. B. Roberts, J. R. Ser, T. D. Kocher, Science 326 , 998
   (2009).


7. A. E. Wright et al., Nat. Commun. 8 , 14251 (2017).


8. S. Ponnikas, H. Sigeman, J. K. Abbott, B. Hansson, Trends
   Genet. 34 , 492 (2018).


9. N. Perrin, Philos. Trans. R. Soc. London Ser. 376 ,
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10. A. Muyle et al., PLOS Biol. 10 , e1001308 (2012).


11. H. Martin et al., Genome Biol. Evol. 11 , 350 (2019).


12. T. Lenormand, F. Fyon, E. Sun, D. Roze, Curr. Biol. 30 ,
    3001 (2020).

10.1126/science.abn7410

Male-determining gene

Male-beneficial gene

Recombination

shutdown locks in

male-determining,

male-beneficial

combination

Nonrecombining region

accumulates deleterious

mutations...

Dosage compensation

Classical

model

Lenormand and

Roze’s model

Deleterious mutations

Trans-regulator

Weakly expressed

genes accumulate

deleterious mutations

Dosage compensation

Recombination shutdown

Recombination

shutdown locks in

low-mutation tract

Cis-regulatory divergence

leads to lower expression

of genes on proto-Y

Cis-regulator

Coding gene

...leading to reduced

gene expression.

Proto-X chromosome

Proto-Y chromosome

Gene

degradation

Gene

degradation

Two models of sex chromosome evolution

The classical model (left) is based on sexually antagonistic selection, whereas Lenormand and Roze’s new

model (right) is based on the regulation of gene expression.