Further to an earlier response by AJR Hickey on the forum (Heredity, in press) to Berlin et al.'s paper on low mitochondrial diversity in birds, Nick Lane now contributes his thoughts on the subject.

Paper by Berlin et al http://www.nature.com/hdy/journal/v99/n4/abs/6801014a.html

News and Commentary by G A B Marais http://www.nature.com/hdy/journal/v99/n4/full/6801034a.html

Rapid Correspondence by A J R Hickey http://blogs.nature.com/hdy/inherentlyresponsive/2007/11/rapid_correspondence_mitochondrial_dna_p_1.html#more

Low variability on the W chromosome in birds is more likely to indicate selection on mitochondrial genes

Nick Lane

The energetic efficiency of mitochondria in birds capable of flight (Hickey, 2007) frames two predictions to test whether avian mitochondria are responsible for the low variation of the W chromosome of birds, rather than being passive victims of maternal linkage, as concluded by Berlin et al. (2007).

There is a general, erroneous, assumption that mutations in mtDNA are not subject to intense selection; that mitochondrial genes do no more than ‘housekeeping’. Yet efficient respiration is crucial for cells, and inefficiencies are punished directly through the loss of cytochrome c and apoptosis. As Bazin et al. (2006) point out, “mtDNA appears to be anything but a neutral marker and probably undergoes frequent adaptive evolution.”

The mitochondrial genome is practically immune to decay over evolutionary time, despite a mutation rate that is 10 to 20 times faster than nuclear genes in vertebrates, and little, if any, recombination. Obviously, birds fly as well now as they did 65 million years ago, and need pristine mitochondria to do so. The mitochondrial genome presumably evades decay because it is small and under intense selection pressure. Such selection presumably operates during early embryonic development, where mitochondrial function apparently determines whether an embryo develops further or is eliminated (Dumullard et al., 2007).

The question is, why, in birds, is there so little variety on the W chromosome? In an earlier paper, Berlin et al. express puzzlement, and argue for a selective sweep (but exclude sexual selection) on the W chromosome. They tested this idea in the present paper, arguing that a selective sweep on the W chromosome should be reflected, via strict maternal linkage, in a lower variation of mitochondrial DNA. But as Marais (2007) observes in a commentary, the same argument applies equally in reverse – strong selection on mitochondrial genes should purge the W chromosome of variation.

The high energy demands of flight must place a stronger selection pressure on mitochondrial genes than occurs in flightless animals. The aerobic power of flight muscle in bats and birds is 2.5 to 3 times greater than that of non-flying mammals of similar size (Maina JN, 2000). This extreme aerobic capacity is attained partly by increasing the number of respiratory complexes, and optimising the kinetic properties of key respiratory enzymes. The closer that respiratory function approaches an optimum, the less variation one would expect in mtDNA (either from ‘genetic draft’ or purifying selection). Restricted variation is exactly what Berlin et al. (2007) report.

In the context of optimising mitochondrial genes for high aerobic capacity, it’s an interesting possibility that low rates of free-radical leak in birds (Lambert et al., 2007; Barja, 2007) may have evolved in part to preserve mtDNA adaptations for flight in the face of Hill-Robertson effects; low free-radical leak would then contribute incidentally to the exceptional longevity of birds.

Because the respiratory complexes are encoded by two genomes that must work together (the nuclear and mitochondrial genomes) there is generally very strong selection for intergenomic coadaptation (Burton et al., 2006). Optimising the sequence of mtDNA counts for nothing if the nuclear genes are not under equally stringent selection. This leads to a specific prediction: in birds there should be less variation in nuclear genes that encode mitochondrial respiratory proteins, regardless of chromosomal location. Such restricted variation should apply most to subunits that interact directly with mitochondrial-encoded subunits such as cytochrome c. In contrast, the absence of Hill-Robertson effects on nuclear chromosomes predicts the opposite – there should be more variation in nuclear-encoded respiratory proteins.

A second prediction concerns the mitochondrial bottleneck. During embryonic development, the bottleneck lowers mtDNA diversity by restricting the copy-number of mtDNA to a bare minimum in primordial oocytes, then amplifying this tiny population to 100,000 copies in the mature oocyte (Shoubridge EA and Wai, 2007). As a result, individual oocytes are typically homoplasmic for mtDNA, the function of which is presumably subjected to selection during embryonic development.

The stringency of the mitochondrial bottleneck varies with factors like litter size (Krakauer and Mira, 1999). In principle, the bottleneck should also vary with aerobic capacity. High aerobic capacity requires rigorous mitochondrial selection, demanding a tighter bottleneck. If there is heavier selection on mtDNA in birds than in mammals, there should also be a tighter bottleneck (specifically fewer copies of the mitochondrial genome in primordial oocytes). If this is the case, the lack of variation on the W chromosome are more likely to indicate to Hill-Robertson effects resulting from selection on mitochondrial genes.

Nick Lane is at the Royal Free and UCL Medical School, UCL, London

email: n.lane@medsch.ucl.ac.uk

Barja J (2007) Mitochondrial oxygen consumption and reactive oxygen species production are independently modulated: Implications for aging studies. Rejuv Res 10, 215-223.

Bazin E, Glémin S, Galtier N (2006) Population size does not influence mitochondrial genetic diversity in animals. Science 312, 570-2.

Berlin S, Tomaras D, Charlesworth B (2007) Low mitochondrial variability in birds may indicate Hill-Robertson effects on the W chromosome. Heredity 99, 389-396.

Burton RS, Ellison CK, Harrison JS (2006) The sorry state of F2 hybrids: consequences of rapid mitochondrial DNA evolution in allopatric populations. Am Nat 168 (Suppl 6), S14-24.

Dumullard R, Duchen M, Carroll J (2007) The role of mitochondrial function in the oocyte and embryo. Curr Top Dev Biol 77, 21-49.

Hickey AJR (2007) An alternate explanation for low mtDNA diversity in birds: an age-old solution? Heredity (in press).

Krakauer DC, Mira A (1999) Mitochondria and germ-cell death. Nature 400, 125-6.

Lambert AJ, Boysen HM, Buckingham JA et al. (2007) Low rates of hydrogen peroxide production by isolated heart mitochondria associate with long maximum lifespan in vertebrate homeotherms. Aging Cell 6, 607-18.

Maina JN (2000) What it takes to fly: the structural and functional respiratory refinements in birds and bats. J Exp Biol 203, 3045-64.

Marais GAB (2007) The Hill-Robertson effects extend from nucleus to mitochondria. Heredity 99, 357-358.

Shoubridge EA, Wai T (2007) Mitochondrial DNA and the mammalian oocyte. Curr Top Dev Biol 77, 87-111.

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After reading with interest an article by Berlin et al. (Heredity 99, 389-396) on mitochondiral variability in birds, Anthony Hickey proposes an alternative interpretation to the data showing low mtDNA diversity, which they attributed to Hill-Robertson effects.

Paper by Berlin et al http://www.nature.com/hdy/journal/v99/n4/abs/6801014a.html

News and Commentary by G A B Marais http://www.nature.com/hdy/journal/v99/n4/full/6801034a.html

An alternate explanation for low mtDNA diversity in birds: an age-old solution?

Anthony J R Hickey

A recent article by Berlin et al. (2007) (also reviewed by Marais (Marais, 2007)) reported that the low mitochondrial variability in birds (relative to mammals) is most easily explained by Hill–Robertson effects on the W chromosome. These authors suggest selection and linkage between the W chromosome (in heterogametic females) and mtDNA act to lower avian mtDNA diversity. This may well be correct; however a well known biological phenomenon which appears unique to birds was excluded from these analyses, and may in fact provide a much simpler and more plausible explanation.
By comparison to mammals, birds are remarkable in several physiological parameters such as athletic performance, capacity to regenerate neuronal damage and their high respiratory efficiencies. However, perhaps more remarkable are several metabolic avian features. Birds have metabolic rates that are 2-2.5 fold greater, and estimated lifetime energy expenditures 15 times that of mammals of equivalent body mass. Not only do birds maintain body temperatures 3oC hotter than mammals, but many birds have blood glucose levels two to four times that of mammals, which in part defines them as diabetic (Holmes et al., 2001). This last feature occurs without the associated pathological complications seen in mammals and highlights considerable protection from oxidative damage.
With few exceptions, birds are also very long living relative to body mass, as many birds live three times longer, or more, than mammals of equivalent mass, and birds age slower at the cellular level (Holmes et al., 2001). Parrots may live over one hundred years, and even the tiny 5 gram Broad-billed hummingbird (Selasphorus platycercus) can live for 14 years (Holmes and Austad, 1995), while the maximum recorded life span of a 20 gram house mouse is only 4 years (Holmes et al., 2001). Zoo and wild tagging data also can mostly eliminate confounding influences of reduced predation through flight (Ricklefs, 1998), and the “exception species”, which are generally domesticated species, still live relatively long (e.g. chickens 20 years, Cortunix quail 6-7 years) (Holmes and Austad, 1995).
Just how birds achieve such exemplary resistance to age appears to be largely explained by different mitochondrial properties. In mammals 2-4% of all consumed oxygen is released as reactive oxygen species (ROS, e.g. superoxide O2-., hydroxyl radical OH-, hydrogen peroxide H2O2) from the electron transport system (ETS) complexes I and III. In health (and more so with numerous pathologies) mitochondria are generally the largest source of ROS (Turrens, 2003). Avian mitochondria produce considerably less ROS than mammalian mitochondria, with pigeon liver and heart mitochondria producing up to 10-fold less H2O2 than rats (this depends on respiration state, and ROS predominates from complexes I and III as O2-., which is converted to H2O2, (Barja, 2004; Herrero and Barja, 1997)). Furthermore, parrots and canaries show considerable resistance to lipid peroxidation relative to rodents, and isolated kidney epithelial cells from other long-lived bird species are much more resilient to pro-oxidant challenge by paraquat, H2O2 and 95% O2 with markedly less DNA damage than mouse cells (Ogburn et al., 1988). The differences between birds and mammals should not also be assumed to be adaptive. ROS release is not necessarily a byproduct of less efficient ETS function, as ROS provides feedback to cells and mitochondria (Barja, 2004), which explains why antioxidants can often be of detriment (Lane, 2005). These data do however illustrate increased ROS protection and lower ROS production in numerous bird species, which results in less DNA damage (Barja, 2004).
These avian physiological features were overlooked by Berlin et al. (2007). This is surprising given that the mitochondrial ETS is juxtaposed to mtDNA, and that ETS derived ROS makes the greatest contribution to mtDNA damage, and hence diversity (Barja, 2004). Admittedly ROS production would be a difficult parameter to measure for many species, although ROS production correlates more tightly with longevity than body mass (Barja, 2004). Therefore, correlation of π with mammalian and avian longevity may provide greater insight (note that this assumes the metabolic theory of ageing). Potentially the lower mitochondrial ROS output of bird mitochondria may provide another and potentially stronger physiological explanation for the low mtDNA diversity of birds.

AJR Hickey is at the School of Biological Sciences, University of Auckland, New Zealand.

email: a.hickey@auckland.ac.nz

Barja G (2004) Free radicals and ageing. Trends in Neurosciences 27, 3602-3607.
Berlin S, Tomaras D, Charlesworth B (2007) Low mitochondrial variability in birds may indicate Hill–Robertson effects on the W chromosome. Heredity 99, 389-396.
Herrero A, Barja G (1997) Sites and mechanisms responsible for the low rate of free radical production of heart mitochondria in the long lived pigeon. Mech. Age. Dev. 98, 95-111.
Holmes DJ, Austad SN (1995) Birds as models for the comparative biology of ageing: a prospectus. J. Gerontol. Biol. Sci. 50A, B59-B66.
Holmes DJ, Flückiger R, Austad SN (2001) Comparative biology of ageing in birds: an update. Exp. Gerontol. 36, 869-883.
Lane N (2005) Power, sex and suicide: mitochondria and the meaning of life. Oxford University Press New York
Marais GAB (2007) The Hill-Robertson effects extend from nucleus to mitochondria. Heredity 99, 357-358.
Ogburn CE, Austad SN, Holmes DJ, et al. (1988) Culture renal epithelial cells from birds and mice: enhanced resistance of avian cells to oxidative stress and DNA damage. J. Gerontol. Biol. Sci. 53A, B287-BB229.
Ricklefs RE (1998) Evolutionary theories of ageing: confirmation of a fundamental prediction, with implications for the genetic basis and evolution of life span. Am. Nat. 122, 22-44.
Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J. Physiol. (Lond) 552, 335-344.

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