Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. Mitochondrial DNA (mtDNA) encodes three COX subunits (I-III) and nuclear DNA (nDNA) encodes ten. In addition, ancillary proteins are required for the correct assembly and function of COX (refs 2, 3, 4, 5, 6). Although pathogenic mutations in mtDNA-encoded COX subunits have been described, no mutations in the nDNA-encoded subunits have been uncovered in any mendelian-inherited COX deficiency disorder. In yeast, two related COX assembly genes, SCO1 and SCO2 (for synthesis of cytochrome c oxidase), enable subunits I and II to be incorporated into the holoprotein. Here we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency. Immunohistochemical studies implied that the enzymatic deficiency, which was most severe in cardiac and skeletal muscle, was due to the loss of mtDNA-encoded COX subunits. The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome.

The interplay of divergent selection and gene flow is key to understanding how populations adapt to local environments and how new species form. Here, we use DNA polymorphism data and genome-wide variation in recombination rate to jointly infer the strength and timing of selection, as well as the baseline level of gene flow under various demographic scenarios. We model how divergent selection leads to a genome-wide negative correlation between recombination rate and genetic differentiation among populations. Our theory shows that the selection density (i.e., the selection coefficient per base pair) is a key parameter underlying this relationship. We then develop a procedure for parameter estimation that accounts for the confounding effect of background selection. Applying this method to two datasets from Mimulus guttatus, we infer a strong signal of adaptive divergence in the face of gene flow between populations growing on and off phytotoxic serpentine soils. However, the genome-wide intensity of this selection is not exceptional compared with what M. guttatus populations may typically experience when adapting to local conditions. We also find that selection against genomewide introgression from the selfing sister species M. nasutus has acted to maintain a barrier between these two species over at least the last 250 ky. Our study provides a theoretical framework for linking genome-wide patterns of divergence and recombination with the underlying evolutionary mechanisms that drive this differentiation.speciation with gene flow | local adaptation | recombination | divergence | Mimulus E stimating the timing and strength of divergent selection is fundamental to understanding the evolution and persistence of organismal diversity (1-3). Genes underlying local adaptation and speciation act as barriers to gene flow, such that genetic divergence around these loci is higher compared with the rest of the genome. However, a framework that explicitly links observable patterns of DNA polymorphism with the underlying evolutionary mechanisms and allows for robust parameter inference has so far been missing (4).One way of studying adaptive genomic divergence in the face of gene flow is to apply methods for demographic inference to scenarios of speciation (e.g., refs. 5 and 6). This approach allows dating population splits and inferring the presence or absence of gene flow, yet generally does not explicitly account for natural selection (but see ref. 7). Another approach is to scan genomes for loci that are statistical outliers of divergence among populations. These scans are used to identify candidate loci underlying speciation or local adaptation (e.g., refs. 8 and 9) and include the search for so-called genomic islands of divergence (e.g., ref. 10) (i.e., extended genomic regions of elevated divergence). Methods of this type can be confounded by other modes of selection, as well as demography, and will always propose a biased subset of candidate loci (11,12).A third approach is to test for a negative correlation between abso...

The interplay of divergent selection and gene flow is key to understanding how populations adapt to local environments and how new species form. Here, we use DNA polymorphism data and genome-wide variation in recombination rate to jointly infer the strength and timing of selection, as well as the baseline level of gene flow under various demographic scenarios. We model how divergent selection leads to a genome-wide negative correlation between recombination rate and genetic differentiation among populations. Our theory shows that the selection density, i.e. the selection coefficient per base pair, is a key parameter underlying this relationship. We then develop a procedure for parameter estimation that accounts for the confounding effect of background selection. Applying this method to two datasets from Mimulus guttatus, we infer a strong signal of adaptive divergence in the face of gene flow between populations growing on and off phytotoxic serpentine soils. However, the genome-wide intensity of this selection is not exceptional compared to what M. guttatus populations may typically experience when adapting to local conditions. We also find that selection against genome-wide introgression from the selfing sister species M. nasutus has acted to maintain a barrier between these two species over at least the last 250 ky. Our study provides a theoretical framework for linking genome-wide patterns of divergence and recombination with the underlying evolutionary mechanisms that drive this differentiation.

23Spatially varying selection is a critical driver of adaptive differentiation. Yet, there are few 24 examples where the fitness effects of naturally segregating variants that contribute to local 25 adaptation have been measured in the field. This project investigates the genetic basis of 26 adaption to serpentine soils in Mimulus guttatus. Reciprocal transplant studies show that 27 serpentine and non-serpentine populations of M. guttatus are genetically differentiated in their 28 ability to survive on serpentine soils. We mapped serpentine tolerance by performing a bulk 29 segregant analysis on F2 survivors from a field transplant study and identify a single QTL 30 where individuals that are homozygous for the non-serpentine allele do not survive on 31 serpentine soils. This same QTL controls serpentine tolerance in a second, geographically 32 distant population. A common garden study where the two serpentine populations were grown 33 on each other's soil finds that one of the populations has significantly lower survival on this 34"foreign" serpentine soil compared to its home soil. So, while these two populations share a 35 major QTL they either differ at other loci involved in serpentine adaptation or have different 36 causal alleles at this QTL. This raises the possibility that serpentine populations may not be 37 broadly tolerant to serpentine soils but may instead be locally adapted to their particular patch. 38Nevertheless, despite the myriad chemical and physical challenges that plants face in serpentine 39 habitats, adaptation to these soils in M. guttatus has a simple genetic basis. 40 41

Spatially varying selection is a critical driver of adaptive differentiation. Yet, there are few examples where the fitness effects of naturally segregating variants that contribute to local adaptation have been measured in the field. Plant adaptation to harsh soil habitats provides an ideal study system for investigating the genetic basis of local adaptation. The work presented here identifies a major locus underlying adaptation to serpentine soils in Mimulus guttatus and estimates the strength of selection on this locus in native field sites. Reciprocal transplant and common‐garden studies show that serpentine and nonserpentine populations of M. guttatus differ in their ability to survive on serpentine soils. We directly mapped these field survival differences by performing a bulk segregant analysis with F2 survivors from a field transplant study and identify a single QTL where individuals that are homozygous for the nonserpentine allele do not survive on serpentine soils. Genotyping the survivors from an independent mapping population reveals that this same QTL controls serpentine tolerance in a second, geographically distant population. Finally, we show that this QTL controls tolerance to soil properties, as opposed to some other aspect of the field sites that may differ, by performing a laboratory‐based common‐garden experiment in native serpentine soils that replicates the survival differences observed in the field. These results indicate that despite the myriad chemical and physical challenges plants face in serpentine habitats, adaptation to these soils in M. guttatus has a simple genetic basis.