Examining marginal sequence relationships

Frequently, diverse protein families contain members that will produce pair-wise similarity scores with expectation values > 0.05. How can we tell if sequences with high, but not statistically significant similarity scores, are related to the query sequence?

If the family is large, a relatively simple test is available. Simply perform additional searches using the sequences with marginal similarity scores. Thus, in the search below with the bacterial DCMA_METSP sequence shows clearly that this protein belongs to the glutathione transferase superfamily. All of the sequences that with statistically significant similarity scores belong to the family.

The best scores are:                                s-w Z-score E(43470)
DCMA_METSP DICHLOROMETHANE DEHALOGENASE (EC 4.5.1. 1982 2721.7   0
GTTR_RAT GLUTATHIONE S-TRANSFERASE YRS-YRS (EC 2.5  344  463.2 2.3e-19
GTT1_RAT GLUTHATHIONE S-TRANSFERASE 5 (EC 2.5.1.18  330  444.1 2.7e-18
GT1_MUSDO GLUTATHIONE S-TRANSFERASE 1 (EC 2.5.1.18  271  364.0 7.9e-14
GT1_DROME GLUTATHIONE S-TRANSFERASE 1-1 (EC 2.5.1.  231  308.7 9.4e-11
GT32_MAIZE GLUTATHIONE S-TRANSFERASE III (EC 2.5.1  204  271.0 1.2e-08

In contrast, a search with the yeast isopentyl transferase, the highest scoring unrelated sequence, shows high (but not statistically significant) with a variety of unrelated sequences, as would be expected by chance.

The best scores are:                              s-w Z-score E(43470)
MOD5_YEAST TRNA ISOPENTENYLTRANSFERASE (EC 2.5.1.8 2876 3535.1   0
MIAA_AGRTU TRNA DELTA(2)-ISOPENTENYLPYROPHOSPHATE   436  527.2  6.4e-23
MIAA_ECOLI TRNA DELTA(2)-ISOPENTENYLPYROPHOSPHATE   397  478.4  3.3e-20
MIAA_SALTY TRNA DELTA(2)-ISOPENTENYLPYROPHOSPHATE   139  172.2  0.004
GTB3_MOUSE GLUTATHIONE S-TRANSFERASE GT9.3 (EC 2.5  118  137.9  0.31
G6PD_ECOLI GLUCOSE-6-PHOSPHATE 1-DEHYDROGENASE (EC  119  130.9  0.76
GTB1_CRILO GLUTATHIONE S-TRANSFERASE Y1 (EC 2.5.1.  110  128.0  1.1
CAMT_PETCR CAFFEOYL-COA O-METHYLTRANSFERASE (EC 2.  107  123.2  2.0
GTMU_MESAU GLUTATHIONE S-TRANSFERASE (EC 2.5.1.18)  104  120.6  2.8
ACCO_PERAE 1-AMINOCYCLOPROPANE-1-CARBOXYLATE OXIDA  107  120.4  2.9
YIK4_YEAST HYPOTHETICAL 59.2 KD PROTEIN IN PFK26-S  110  119.4  3.3
G6PD_ERWCH GLUCOSE-6-PHOSPHATE 1-DEHYDROGENASE (EC  109  118.5  3.7
RASX_XENLA TRANSFORMING PROTEIN P21/K-RAS.          101  118.4  3.8
GNTV_ECOLI GLUCONOKINASE (EC 2.7.1.12) (GLUCONATE   100  117.2  4.4
TFC1_YEAST TRANSCRIPTION FACTOR TAU 95 KD SUBUNIT   110  116.9  4.6
GTM4_HUMAN GLUTATHIONE S-TRANSFERASE MUSCLE (EC 2.  101  116.9  4.6

While there are several glutathione transferases on this list, none has a statistically signficant similarity score. The presence of several family members is not very informative because they are all very closely related.