Combinatorial effects on clumped isotopes and their significance in biogeochemistry

A new paper from Laurence Yeung on the fundamentals of “clumped-isotope” fractionation, was recently accepted in Geochimica et Cosmochimica Acta. It shows, through simple theoretical arguments, the factors influencing the occurrence of rare-isotope pairs in molecules when they are made. One might be able to base future tracers of biogeochemistry on these principles.

One of the findings is also a convenient practical summary: When playing Craps, never bet on snake eyes if you suspect the dice are loaded―it, along with the other hard rolls (double threes, double fours, etc.) are less likely to come up when the dice are not evenly weighted.

doi: 10.1016/j.gca.2015.09.020


The arrangement of isotopes within a collection of molecules records their physical and chemical histories. Clumped-isotope analysis interrogates these arrangements, i.e., how often rare isotopes are bound together, which in many cases can be explained by equilibrium and/or kinetic isotope fractionation. However, purely combinatorial effects, rooted in the statistics of pairing atoms in a closed system, are also relevant, and not well understood. Here, I show that combinatorial isotope effects are most important when two identical atoms are neighbors on the same molecule (e.g., O2, N2, and D-D clumping in CH4). When the two halves of an atom pair are either assembled with different isotopic preferences or drawn from different reservoirs, combinatorial effects cause depletions in clumped-isotope abundance that are most likely between zero and –1‰, although they could potentially be –10‰ or larger for D-D pairs. These depletions are of similar magnitude, but of opposite sign, to low-temperature equilibrium clumped-isotope effects for many small molecules. Enzymatic isotope-pairing reactions, which can have site-specific isotopic fractionation factors and atom reservoirs, should express this class of combinatorial isotope effect, although it is not limited to biological reactions. Chemical-kinetic isotope effects, which are related to a bond-forming transition state, arise independently and express second-order combinatorial effects related to the abundance of the rare isotope. Heteronuclear moeties (e.g., C–O and C–H), are insensitive to direct combinatorial influences, but secondary combinatorial influences are evident.

In general, both combinatorial and chemical-kinetic factors are important for calculating and interpreting clumped-isotope signatures of kinetically controlled reactions. I apply this analytical framework to isotope-pairing reactions relevant to geochemical oxygen, carbon, and nitrogen cycling that may be influenced by combinatorial clumped-isotope effects. These isotopic signatures, manifest as either directly bound isotope “clumps” or as features of a molecule’s isotopic anatomy, are linked to molecular mechanisms and may eventually provide additional information about biogeochemical cycling on environmentally relevant spatial scales.

Read more about the research in the Yeung Lab at

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