Haldane's rule

Haldane's rule is an observation about the early stage of speciation, formulated in 1922 by
the British evolutionary biologist J.B.S. Haldane, that states that if in a species hybrid only
one sex is inviable or sterile, that sex is more likely to be the heterogametic sex. The
heterogametic sex is the one with two different sex chromosomes; in therian mammals,[a] for
example, this is the male.[2] In humans, barring
intersex conditions and
other unusual states, it is
the male that is
Contents heterogametic, with XY
sex chromosomes.
Overview
Hypotheses
Exceptions
Notes
References
Further reading

Overview
Haldane himself described the rule as:

When in the F1 offspring of two different animal races one sex is absent, rare, or sterile, that sex is the
heterozygous sex (heterogametic sex).[3]

Haldane's rule applies to the vast majority of heterogametic organisms. This includes the case where two species make secondary
contact in an area of sympatry and form hybrids after allopatric speciation has occurred.

The rule includes both male heterogametic (XY or XO-type sex determination, such as found in mammals and Drosophila fruit
flies) and female heterogametic (ZW-type sex determination, as found in birds and butterflies), and some dioecious plants such as
campions.[4]

Hybrid dysfunction (sterility and inviability) is a major form of post-zygotic reproductive isolation, which occurs in early stages
of speciation. Evolution can produce a similar pattern of isolation in a vast array of different organisms. However, the actual
mechanisms leading to Haldane's rule in different taxa remain largely undefined.

Hypotheses
Many different hypotheses have been advanced to address the evolutionary mechanisms to produce Haldane's rule. Currently, the
most popular explanation for Haldane's rule is the composite hypothesis, which divides Haldane's rule into multiple subdivisions,
including sterility, inviability, male heterogamety, and female heterogamety. The composite hypothesis states that Haldane's rule
in different subdivisions has different causes. Individual genetic mechanisms may not be mutually exclusive, and these
mechanisms may act together to cause Haldane's rule in any given subdivision.[5][6] In contrast to these views that emphasise
genetic mechanisms, another view hypothesizes that population dynamics during population divergence may cause Haldane's
rule.[7]

The main genetic hypotheses are:

Dominance: Heterogametic hybrids are affected by all X-linked alleles (be they recessive or dominant) causing
incompatibilities due to divergent alleles being brought together. However, homogametic hybrids are only affected
by dominant deleterious X-linked alleles. Heterogametic hybrids, which carry only a single copy of a given X-
linked gene, will be affected by mutations regardless of dominance. Thus, an X-linked incompatibility between
diverging populations is more likely to be expressed in the heterogametic sex than in the homogametic sex.
The "faster male": Male genes are thought to evolve faster due to sexual selection.[6] As a result, male sterility
becomes more evident in male heterogametic taxa (XY sex determination). This hypothesis conflicts with
Haldane's rule in male homogametic taxa, in which females are more affected by hybrid inferiority. It therefore
only applies to male sterility in taxa with XY sex determination, according to the composite theory.
Meiotic drive: In hybrid populations, selfish genetic elements inactivate sperm cells (i.e.: an X-linked drive factor
inactivates a Y-bearing sperm and vice versa).
The "faster X": Genes on hemizygous chromosomes may evolve more quickly by enhancing selection on
possible recessive alleles causing a larger effect in reproductive isolation.[8]
Differential selection: Hybrid incompatibilities affecting the heterogametic sex and homogametic sex are
fundamentally different isolating mechanisms, which makes heterogametic inferiority (sterility/inviability) more
visible or preserved in nature.[7]
Data from multiple phylogenetic groups support a combination of dominance and faster X-chromosome theories.[9] However, it
has recently been argued that dominance theory can not explain Haldane's rule in marsupials since both sexes experience the
same incompatibilities due to paternal X-inactivation in females.[10]

The dominance hypothesis is the core of the composite theory, and X-linked recessive/dominance effects have been demonstrated
in many cases to cause hybrid incompatibilities. There is also supporting evidence for the faster male and meiotic drive
hypotheses. For example, a significant reduction of male-driven gene flow is observed in Asian elephants, suggesting faster
evolution of male traits.[11]

Although the rule was initially stated in context of diploid organisms with chromosomal sex determination, it has recently been
argued that it can be extended to certain species lacking chromosomal sex determination, such as haplodiploids[12] and
hermaphrodites.[9]

Exceptions
There are notable exceptions to Haldane's rule, where the homogametic sex turns out to be inviable while the heterogametic sex is
viable and fertile. This is seen in Drosophila fruit flies.[13][14]

Notes
a. Unlike other mammals, monotremes have more than two different sex chromosomes: The platypus has five
pairs, as do female echidnas. Male echidnas have nine.[1]

References
1. Deakin, J.E.; Graves, J.A.M.; Rens, W. (2012). "The Evolution of Marsupial and Monotreme Chromosomes".
Cytogenetic and Genome Research. 137 (2–4): 113–129. doi:10.1159/000339433 (https://doi.org/10.1159%2F00
0339433). PMID 22777195 (https://www.ncbi.nlm.nih.gov/pubmed/22777195).
2. Turelli, M.; Orr, H.A. (May 1995). "The dominance theory of Haldane's rule" (https://www.ncbi.nlm.nih.gov/pmc/art
icles/PMC1206564). Genetics. 140 (1): 389–402. PMC 1206564 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC
1206564). PMID 7635302 (https://www.ncbi.nlm.nih.gov/pubmed/7635302).
 3. Haldane, J.B.S. (1922). "Sex ratio and unisexual sterility in hybrid animals" (https://zenodo.org/record/1428440/fil
es/article.pdf) (PDF). J. Genet. 12 (2): 101–109. doi:10.1007/BF02983075 (https://doi.org/10.1007%2FBF029830
75).
4. Brothers, Amanda N.; Delph, Lynda F. (2010). "Haldane's rule is extended to plants with sex chromosomes".
Evolution. 64 (12): 3643–3648. doi:10.1111/j.1558-5646.2010.01095.x (https://doi.org/10.1111%2Fj.1558-5646.2
010.01095.x). PMID 20681984 (https://www.ncbi.nlm.nih.gov/pubmed/20681984).
5. Orr, H.A. (1993). "Haldane's rule has multiple genetic causes". Nature. 361 (6412): 532–533.
Bibcode:1993Natur.361..532O (https://ui.adsabs.harvard.edu/abs/1993Natur.361..532O). doi:10.1038/361532a0
(https://doi.org/10.1038%2F361532a0). PMID 8429905 (https://www.ncbi.nlm.nih.gov/pubmed/8429905).
6. Wu, C.-I.; Davis, A. W. (1993). "Evolution of postmating reproductive isolation: The composite nature of
Haldane's rule and its genetic bases". The American Naturalist. 142 (22): 187–212. doi:10.1086/285534 (https://d
oi.org/10.1086%2F285534). JSTOR 2462812 (https://www.jstor.org/stable/2462812). PMID 19425975 (https://ww
w.ncbi.nlm.nih.gov/pubmed/19425975).
7. Wang, R. (2003). "Differential strength of sex-biased hybrid inferiority in impeding gene flow may be a cause of
Haldane's rule". Journal of Evolutionary Biology. 16 (2): 353–361. doi:10.1046/j.1420-9101.2003.00528.x (https://
doi.org/10.1046%2Fj.1420-9101.2003.00528.x). PMID 14635874 (https://www.ncbi.nlm.nih.gov/pubmed/1463587
4).
8. Charlesworth, B.; Coyne, J.A.; Barton, N.H. (1987). "The relative rates of evolution of sex chromosomes and
autosomes". The American Naturalist. 130 (1): 113–146. doi:10.1086/284701 (https://doi.org/10.1086%2F28470
1). JSTOR 2461884 (https://www.jstor.org/stable/2461884).
9. Schilthuizen, M.; Giesbers, M.C.; Beukeboom, L.W. (2011). "Haldane's rule in the 21st century" (https://www.ncbi.
nlm.nih.gov/pmc/articles/PMC3178397). Heredity. 107 (2): 95–102. doi:10.1038/hdy.2010.170 (https://doi.org/10.
1038%2Fhdy.2010.170). PMC 3178397 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178397).
PMID 21224879 (https://www.ncbi.nlm.nih.gov/pubmed/21224879).
10. Watson, E.; Demuth, J. (2012). "Haldane's rule in marsupials: What happens when both sexes are functionally
hemizygous?" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331990). Journal of Heredity. 103 (3): 453–458.
doi:10.1093/jhered/esr154 (https://doi.org/10.1093%2Fjhered%2Fesr154). PMC 3331990 (https://www.ncbi.nlm.n
ih.gov/pmc/articles/PMC3331990). PMID 22378959 (https://www.ncbi.nlm.nih.gov/pubmed/22378959).
11. Fickel, J.; Lieckfeldt, D.; Ratanakorn, P.; Pitra, C. (2007). "Distribution of haplotypes and microsatellite alleles
among Asian elephants (Elephas maximus) in Thailand". European Journal of Wildlife Research. 53 (4): 298–
303. doi:10.1007/s10344-007-0099-x (https://doi.org/10.1007%2Fs10344-007-0099-x).
12. Koevoets, T.; Beukeboom, L. W. (2009). "Genetics of postzygotic isolation and Haldane's rule in haplodiploids".
Heredity. 102 (1): 16–23. doi:10.1038/hdy.2008.44 (https://doi.org/10.1038%2Fhdy.2008.44). PMID 18523445 (ht
tps://www.ncbi.nlm.nih.gov/pubmed/18523445).
13. Sawamura, K. (1996). "Maternal effect as a cause of exceptions for Haldane's rule" (https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC1207293). Genetics. 143 (1): 609–611. PMC 1207293 (https://www.ncbi.nlm.nih.gov/pmc/artic
les/PMC1207293). PMID 8722809 (https://www.ncbi.nlm.nih.gov/pubmed/8722809).
14. Ferree, Patrick M.; Barbash, Daniel A. (2009). Noor, Mohamed A.F. (ed.). "Species-specific heterochromatin
prevents mitotic chromosome Segregation to Cause hybrid lethality in Drosophila" (https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC2760206). PLOS Biology. 7 (10): e1000234. doi:10.1371/journal.pbio.1000234 (https://doi.org/1
0.1371%2Fjournal.pbio.1000234). PMC 2760206 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760206).
PMID 19859525 (https://www.ncbi.nlm.nih.gov/pubmed/19859525).

Further reading
Coyne, J.A. (1985). "The genetic basis of Haldane's rule". Nature. 314 (6013): 736–738.
Bibcode:1985Natur.314..736C (https://ui.adsabs.harvard.edu/abs/1985Natur.314..736C). doi:10.1038/314736a0
(https://doi.org/10.1038%2F314736a0). PMID 3921852 (https://www.ncbi.nlm.nih.gov/pubmed/3921852).
Forsdyke, Donald (2005). "Haldane's rule" (http://post.queensu.ca/~forsdyke/haldane1.htm). Retrieved
11 October 2006.
Naisbit, Russell E.; Jiggins, Chris D.; Linares, Mauricio; Salazar, Camilo; Mallet, James (2002). "Hybrid sterility,
Haldane's rule, and speciation in Heliconius cydno and H. melpomene" (https://www.ncbi.nlm.nih.gov/pmc/article
 s/PMC1462209). Genetics. 161 (4): 1517–1526. PMC 1462209 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1
462209). PMID 12196397 (https://www.ncbi.nlm.nih.gov/pubmed/12196397).

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